var title_f6_8_6272="Cholesteatoma pars flaccida";

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" Acquired cholesteatoma of the pars flaccida with chronic purulent drainage",
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" </div>",
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" Acquired cholesteatoma of the pars flaccida. This lesion presented with
chronic purulent drainage and a white mass behind the drum.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Glenn C Isaacson, MD, FAAP, FACS.",
" </div>",
" </div>",
" </div>",
" </div>",
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var title_f6_8_6274="Patient information: Vesicoureteral reflux in adults (The
Basics)";
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JavaScript is required in order for our site to behave correctly. Please enable
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" ^{",
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" &copy;2013 UpToDate",
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" </span>",
" <h4>",
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" View All",
" </a>",
" </span>",
" </h4>",
" <ul>",
" <li>",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?29/0/29696\">",
" Urinary tract in adults",
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" </h4>",
" <dl>",
" <dt class=\"basics\">",
" The Basics",
" </dt>",
" <dd>",
" <a href=\"UTD.htm?16/0/16386\">",
" Patient information: Neurogenic bladder in adults (The Basics)",
" </a>",
" </dd>",
" <dd>",
" <a href=\"UTD.htm?19/47/20210\">",
" Patient information: Urinary tract infections in adults (The Basics)",
" </a>",
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" Beyond the Basics",
" </dt>",
" <dd>",
" <a href=\"UTD.htm?31/18/32036\">",
" Patient information: Urinary tract infections in adolescents and adults
(Beyond the Basics)",
" </a>",
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" Patient information: Vesicoureteral reflux in adults (The Basics)",
" </div>",
" <span class=\"view\">",
" View in",
" <a class=\"lang\" href=\"./es-419/vesicoureteral-reflux-in-adults-the-basics?
source=topic_page\">",
" Spanish",
" </a>",
" </span>",
" <a class=\"contributor contributor_credentials\" href=\"./authors-and-
editors/patient-information\">",
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" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H18619157\">",
" <span class=\"h1\">",
" What is vesicoureteral reflux?",
" </span>",
" &nbsp;&mdash;&nbsp;Vesicoureteral reflux is a condition that causes some
urine to flow in the wrong direction inside the body. Normally, urine that the
kidneys make flows to the bladder through tubes called &ldquo;ureters.&rdquo; It
then flows from the bladder out of the body. (All the organs that handle urine are
called the &ldquo;urinary tract.&rdquo;) In",
" <strong>",
" </strong>",
" people with vesicoureteral reflux, some of the urine flows backward from the
bladder through the ureters to the kidneys (",
" <a class=\"graphic graphic_figure graphicRef82960 \" href=\"UTD.htm?
29/0/29696\">",
" figure 1",
" </a>",
" ). This can happen in 1 or both of the ureters.",
" </p>",
" <p>",
" This problem is most common in babies and young children. It often gets
better or goes away as the child gets older. But it can also happen in older
children and in adults.",
" </p>",
" <p class=\"headingAnchor\" id=\"H18619174\">",
" <span class=\"h1\">",
" What causes vesicoureteral reflux?",
" </span>",
" &nbsp;&mdash;&nbsp;Vesicoureteral reflux is caused by problems with the
ureters or bladder. Most of the time, people are born with these problems. But the
problems might not be found until the person is an adult. Other times, people who
weren&rsquo;t born with vesicoureteral reflux get it later in life because of
different conditions that affect the urinary tract.",
" </p>",
" <p class=\"headingAnchor\" id=\"H18619189\">",
" <span class=\"h1\">",
" What are the symptoms of vesicoureteral reflux?",
" </span>",
" &nbsp;&mdash;&nbsp;There are no symptoms.",
" </p>",
" <p class=\"headingAnchor\" id=\"H18619204\">",
" <span class=\"h1\">",
" Why would a doctor think I have vesicoureteral reflux?",
" </span>",
" &nbsp;&mdash;&nbsp;Your doctor might think you have vesicoureteral reflux
for different reasons, including:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Frequent urinary tract infections (or &ldquo;UTIs&rdquo;) - These
infections are usually caused by bacteria in the bladder or kidneys. If you get
UTIs often, your doctor might want test you for vesicoureteral reflux. If you have
both conditions at the same time, infected urine could flow backwards to the kidney
and cause damage.&nbsp;",
" </li>",
" <li>",
" Abnormal findings on an imaging test &ndash; People get imaging tests that
take pictures of the inside of the body for different reasons. These tests include
ultrasounds and MRIs. If some part of your urinary tract does not look normal on
one of these tests, your doctor might want to test you for vesicoureteral reflux.",
" </li>",
" <li>",
" High blood pressure &ndash; High blood pressure is very common, especially
in older people and people who are overweight. It usually has nothing to do with
vesicoureteral reflux, but in a few people, the 2 conditions are related. If your
doctor thinks your high blood pressure is not caused by the usual problems, he or
she might want to test you for vesicoureteral reflux.",
" </li>",
" <li>",
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small, flexible tube inside your bladder. Next the doctor fills the bladder with a
special fluid that shows up on X-rays. You then urinate while an X-ray is taken. X-
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" Antibiotics &ndash; Your doctor might want you to take antibiotics every
day, but at a lower dose than if you really had an infection. These medicines can
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the bladder to the kidney.",
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source=see_link\">",
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" </div>",
" <div class=\"lgnd\">",
" Subconjunctival petechiae are prominent in this case of bacterial endocarditis
caused by Staphylococcus aureus.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Jan V Hirschmann. The Skin and Infection: A Color Atlas and Text,
Sanders CV, Nesbitt LT Jr (Eds), Williams &amp; Wilkins, Baltimore, 1995.",
" </div>",
" <div class=\"contractual\">",
" <br/>",
" <a href=\"file://www.lww.com\">",
" file://www.lww.com",
" </a>",
" </div>",
" </div>",
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nGO9IVkaE7LLH/AKxlY527OpX0IHSoWQQBw+9l67WwzMPY9wMVV+1RxupMu0sQP3i7eoPGD1PHb0qVvNjLG
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li7nAVMYB5BPoaybqc7Mlvk+6CabGjzyNLJIcD5j820KB6k1jX1+rOEjxsz949DV2MZVBLi8VcuxOD/ez/A
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0lrElnfMZQdzRyJtdznttz8vp6Vx9lNbynckoknPAVj82CPyAzWrGqsLeWPctyuSSrkqPoO1ZNHfCbZ09lq
Uk/lw35na3Q8TBd7jj5UIznHv2qzJc3E6lEEjEDcrHqD2OfwJ5rk/t9zYpJgDJ4AKbgrA9Ac8ZycVfXUNRu
LgRzFlxklEwoYE9WPscAZ9RSsU29i/MZ0k4iYxsePnO4n1xyfXk0yZ4BdyC4Vm4GFYgsvuc+vXAp8sFyVcQ
xvF8wj2lsnHuccDOOnNQLHGJX81g8vQybt2SDz16c/yppCcrrU9YP/AB7H/d/wqlqP3D/n+KiiuhnlxJLv+
P8A3W/9BqLUf9XZf9dz/KiiqB7iW3/IWg/z2pdU/wBZP9GoorN7f15B9oD/AMfX+f7tVl/5Csf40UUM0WxX
tf8Aj+H+f4mqeT/WyfT+tFFQihV/49h9T/KmSf0/9loopoHuRT/8sf8APYVSXrH/ALpoooWwGVcfcT/f/wA
Kr/8AMRn/AN4/0oopmbKVx99vxrCb/j3b/eFFFXDYmRV1D/Uj/PesR/uL9TRRVmDK1x/qW+lc7c/cP+5RRT
Zi9zl77/Wn6Gq9/wD8fcv1oorWJFQr0UUVZkFSSfci/wB3+poooAsz9fwT+Qrbg/49Iv8Arl/SiispnRDcu
aZ/x+yf7hrZtP8Aj7j+o/nRRXNI7omxH/rIv94/0rrfD/8AyF7f/PY0UVmtzuhsR63/AMgqX/rqP5mpvD//
ACEov+A/1ooqOhb3NY/8hhf+ub/+g1kaH/qJf9//ABoorSmRUP/Z);\">",
" </div>",
" <div class=\"lgnd\">",
" Tinea cruris infection caused by T. rubrum involving the crural fold and
medial aspect of the right thigh.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of John T Crissey, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_8_6276=[""].join("\n");
var outline_f6_8_6276=null;
var title_f6_8_6277="Insulin detemir: Patient drug information";
var content_f6_8_6277=[" <noscript>",
" <div id=\"javascriptDisabled\">",
" It seems to us that you have your JavaScript turned off on your browser.
JavaScript is required in order for our site to behave correctly. Please enable
your JavaScript to continue use our site.",
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" www.uptodate.com",
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" <div id=\"topicContent\">",
" <div id=\"disclaimer\">",
" The content on the UpToDate website is not intended nor recommended as a
substitute",
"for medical advice, diagnosis, or treatment. Always seek the advice of your own
physician or",
"other qualified health care professional regarding any medical questions or
conditions. The",
"use of this website is governed by the",
" <a href=\"/home/terms-use\" target=\"_blank\">",
" UpToDate Terms of Use",
" </a>",
" &copy;2013 UpToDate, Inc.",
" </div>",
" <div id=\"drugTitle\">",
" Insulin detemir: Patient drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
" <div class=\"clear\">",
" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <div id=\"topicText\">",
" <p>",
" (For additional information",
" <a class=\"drug drug_general\" href=\"UTD.htm?24/49/25367?source=see_link\">",
" see \"Insulin detemir: Drug information\"",
" </a>",
" and",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?17/41/18070?
source=see_link\">",
" see \"Insulin detemir: Pediatric drug information\"",
" </a>",
" )",
" </p>",
" <div class=\"list ubnlist drugH1Div drugBrandNames\" id=\"F2110562\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: U.S.",
" </span>",
" <ul>",
" <li>",
" Levemir&reg;;",
" </li>",
" <li>",
" Levemir&reg; FlexPen&reg;",
" </li>",
" </ul>",
" </div>",
" <div class=\"list cbnlist drugH1Div drugBrandNames\" id=\"F2186123\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: Canada",
" </span>",
" <ul>",
" <li>",
" Levemir&reg;",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yya-os drugH1Div\" id=\"F10018691\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What is this drug used for?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2691404",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to lower blood sugar in patients with high blood sugar
(diabetes).",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt coi-os drugH1Div\" id=\"F10018690\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What do I need to tell my doctor before I take this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2702304",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have an allergy to insulin or any other part of this drug.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2705171",
" </span>",
" </span>",
" <span class=\"content\">",
" If you are allergic to any drugs, foods, or other substances. Tell your
doctor about the allergy and what signs you had, like rash; hives; itching;
shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or
any other signs.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yye-os drugH1Div\" id=\"F10018695\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some things I need to know or do while I take this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697780",
" </span>",
" </span>",
" <span class=\"content\">",
" Wear disease medical alert ID (identification).",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696820",
" </span>",
" </span>",
" <span class=\"content\">",
" Do not run out of this drug.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697009",
" </span>",
" </span>",
" <span class=\"content\">",
" If you are 80 or older, use this drug with care. You could be more
sensitive to low blood sugar.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696750",
" </span>",
" </span>",
" <span class=\"content\">",
" Do not drive if your blood sugar has been low. There is a greater chance of
you having a crash.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697282",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have kidney disease, talk with your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697290",
" </span>",
" </span>",
" <span class=\"content\">",
" If you have liver disease, talk with your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698422",
" </span>",
" </span>",
" <span class=\"content\">",
" Check your blood sugar as you have been told by your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698463",
" </span>",
" </span>",
" <span class=\"content\">",
" Have your blood work checked often. Talk with your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698495",
" </span>",
" </span>",
" <span class=\"content\">",
" Have an eye exam and visit the foot doctor every year.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696717",
" </span>",
" </span>",
" <span class=\"content\">",
" Check all drugs you are taking with your doctor. This drug may not mix well
with some other drugs.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" <span class=\"content\">",
" Keep a list of all your drugs (prescription, natural products, vitamins,
OTC) with you. Give this list to your doctor.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697562",
" </span>",
" </span>",
" <span class=\"content\">",
" Limit your drinking of wine, beer, or mixed drinks.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696704",
" </span>",
" </span>",
" <span class=\"content\">",
" Keep workouts the same. More workouts may lower your insulin needs.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697641",
" </span>",
" </span>",
" <span class=\"content\">",
" Tell your doctor if you are pregnant or plan on getting pregnant. You will
need to talk about the benefits and risks of using this drug while you are
pregnant.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2697636",
" </span>",
" </span>",
" <span class=\"content\">",
" Tell your doctor if you are breast-feeding. You will need to talk about any
risks to your baby.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyf-os drugH1Div\" id=\"F10018696\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some side effects of this drug?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698210",
" </span>",
" </span>",
" <span class=\"content\">",
" Low blood sugar may occur. Signs may be dizziness, headache, feeling
sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating.
Keep hard candies, glucose tablets, liquid glucose, or juice on hand for low blood
sugar.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698272",
" </span>",
" </span>",
" <span class=\"content\">",
" Upset stomach or throwing up. Many small meals, good mouth care, sucking
hard, sugar-free candy, or chewing sugar-free gum may help.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698392",
" </span>",
" </span>",
" <span class=\"content\">",
" Weight gain.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698189",
" </span>",
" </span>",
" <span class=\"content\">",
" Irritation where the shot is given.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyh-os drugH1Div\" id=\"F10018698\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" What are some side effects that I need to call my doctor about right away?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698721",
" </span>",
" </span>",
" <span class=\"content\">",
" If you think there has been an overdose, call 1-800-222-1222 (the American
Association of Poison Control Centers), your local poison control center
(file://www.aapcc.org), or emergency room (ER) right away.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699066",
" </span>",
" </span>",
" <span class=\"content\">",
" Signs of an allergic reaction, like rash; hives; itching; red, swollen,
blistered, or peeling skin with or without fever; wheezing; tightness in the chest
or throat; trouble breathing or talking; unusual hoarseness; or swelling of the
mouth, face, lips, tongue, or throat.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699077",
" </span>",
" </span>",
" <span class=\"content\">",
" Signs of infection. These include a fever of 100.5&deg;F (38&deg;C) or
higher, chills, very bad sore throat, ear or sinus pain, cough, more sputum or
change in color of sputum, pain with passing urine, mouth sores, wound that will
not heal, or anal itching or pain.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699111",
" </span>",
" </span>",
" <span class=\"content\">",
" Very low blood sugar or very high blood sugar.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698603",
" </span>",
" </span>",
" <span class=\"content\">",
" Any rash.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2698977",
" </span>",
" </span>",
" <span class=\"content\">",
" Side effect or health problem is not better or you are feeling worse.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyc-os drugH1Div\" id=\"F10018693\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" How is this drug best taken?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2696185",
" </span>",
" </span>",
" <span class=\"content\">",
" Use as you have been told, even if you are feeling better.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699163",
" </span>",
" </span>",
" <span class=\"content\">",
" Do not use out dated insulin.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2807179",
" </span>",
" </span>",
" <span class=\"content\">",
" Do not mix this insulin in the same syringe with other types of insulin.",
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" </li>",
" <li class=\"statement\">",
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" It is given as a shot into the fatty part of the skin.",
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" Spread the shots out from each other. You may give in the same body part,
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" <span class=\"attributes\" style=\"display:none;\">",
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your doctor when it is full.",
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" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
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" &bull;",
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" Follow the diet and workout plan that your doctor told you about.",
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" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s3629482",
" </span>",
" </span>",
" <span class=\"content\">",
" Give a missed shot as soon as you think about it.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s3629483",
" </span>",
" </span>",
" <span class=\"content\">",
" If it is close to the time for your next shot, skip the missed shot and go
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" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s3744606",
" </span>",
" </span>",
" <span class=\"content\">",
" Store unopened vials in a refrigerator or at room temperature. If stored at
room temperature, throw away any part not used after 42 days.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
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" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699216",
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" </span>",
" <span class=\"content\">",
" You may store opened vials at room temperature or in a refrigerator. Throw
away any part not used after 42 days.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
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" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699516",
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" </span>",
" <span class=\"content\">",
" Store opened cartridges at room temperature. Throw away any part not used
after 42 days.",
" </span>",
" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2699284",
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" </span>",
" <span class=\"content\">",
" Protect opened containers from heat.",
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" </li>",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" &bull;",
" </span>",
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" urn:lims:b498:s2699285",
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" </span>",
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" urn:lims:b259:s2699675",
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" If your symptoms or health problems do not get better or if they become
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" </span>",
" <span class=\"link\">",
" urn:lims:b259:s2699673",
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" </li>",
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" <span class=\"attributes\" style=\"display:none;\">",
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" urn:lims:b259:s2699678",
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" urn:lims:b259:s2699709",
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var title_f6_8_6278="Lung ca IV PI";
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" </div>",
" <div class=\"lgnd\">",
" This figure depicts a stage IV cancer. In stage IV cancer, the tumor has
spread (metastasized) somewhere distant from the original tumor. This could include
spread to the other side of the chest or to other places in the body such as the
bones, the brain, the liver or the adrenal glands. Stage IV cancer can also cause
fluid collections to build up inside the chest which are called malignant
effusions.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_8_6278=[""].join("\n");
var outline_f6_8_6278=null;
var title_f6_8_6279="Florid bile duct lesion in PBC - II";
var content_f6_8_6279=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=GAST
%2F66595&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=GAST
%2F66595&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 520px\">",
" <div class=\"ttl\">",
" Florid bile duct lesion in PBC - II",
" </div>",
" <div class=\"cntnt\" style=\"width: 500px; height: 339px; background-image:
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O4RzEpkZ2nb2r0jTbiZ7GEtISSqknvRRWy2Q47F6YB0XcAck1l6qdlzGi8KwBI9aKKtbEs8N8RajeLrt8Uu
ZVzIgO1sZHTFd9Ld3D+GobhpWM0E6pG3TC+nvRRRB6MU90ctas1xc6g0zMxW6dRzjA49KKKKtCP/2Q==);\
">",
" </div>",
" <div class=\"lgnd\">",
" Primary biliary cirrhosis in a 45-year-old woman (high power, H&amp;E). T-
lymphocytes have destroyed adjacent bile duct cells, and there is now a hole in the
epithelial lining that allows bile, with all of its toxic chemicals, to diffuse
into the lamina propria and cause chemical damage. Bile acids, in the concentration
found in bile, are highly toxic to liver tissue.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced from: MacSween RNM, Anthony PP, Scheuer PJ. Pathology of the
Liver, 2nd edition, Churchill Livingstone. Illustration used with the permission of
Elsevier Inc. All rights reserved.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_8_6279=[""].join("\n");
var outline_f6_8_6279=null;
var title_f6_8_6280="Chemotherapy in castrate-resistant prostate cancer";
var content_f6_8_6280=[" <noscript>",
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" <div id=\"topicContent\">",
" <div id=\"topicTitle\">",
" Chemotherapy in castrate-resistant prostate cancer",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
" <a id=\"authors\">",
" </a>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/8/6280/contributors\">",
" Authors",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/8/6280/contributors\">",
" Arif Hussain, MD",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/8/6280/contributors\">",
" Nancy A Dawson, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/8/6280/contributors\">",
" Section Editors",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/8/6280/contributors\">",
" Nicholas Vogelzang, MD",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/8/6280/contributors\">",
" W Robert Lee, MD, MS, MEd",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/8/6280/contributors\">",
" Jerome P Richie, MD, FACS",
" </a>",
" <br/>",
" </div>",
" <div>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/8/6280/contributors\">",
" Deputy Editor",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/8/6280/contributors\">",
" Michael E Ross, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" <div id=\"disclosures\">",
" <a href=\"UTD.htm?6/8/6280/contributor-disclosure\" target=\"_blank\">",
" Disclosures",
" </a>",
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" <div id=\"reviewProcess\">",
" <span>",
" All topics are updated as new evidence becomes available and our",
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" <a href=\"/home/editorial-policy\" target=\"_blank\">",
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" <div id=\"literatureReviewDate\">",
" <span class=\"emphasis\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" <span class=\"pipeSpace\">",
" |",
" </span>",
" <span class=\"emphasis\">",
" This topic last updated:",
" </span>",
" Jan 21, 2013.",
" </div>",
" <div id=\"topicText\">",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;For men with advanced prostate cancer, various hormonal
therapies usually can provide disease control for a substantial period of time.
However, the vast majority of men eventually develop progressive disease that is
resistant to further hormonal treatment. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?1/20/1353?
source=see_link\">",
" \"Initial hormone therapy for metastatic prostate cancer\"",
" </a>",
" .)",
" </p>",
" <p>",
" Prior to the development of the taxanes, cytotoxic chemotherapy was considered
to be relatively ineffective in men with castrate-resistant prostate cancer. In
early trials, objective response rates were 10 to 20 percent, and median survival
generally did not exceed 12 months. However, taxane-based regimens have been
associated with higher rates of objective tumor regression and biochemical
(prostate specific antigen [PSA]) response, as well as longer overall survival.",
" </p>",
" <p>",
" The use of cytotoxic chemotherapy for the treatment of castrate-resistant
prostate cancer will be reviewed here. An overview of the management of advanced
prostate cancer is presented separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/12/10442?
source=see_link\">",
" \"Overview of the treatment of disseminated prostate cancer\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h1\">",
" CHEMOTHERAPY-NAIVE PATIENTS: DOCETAXEL",
" </span>",
" &nbsp;&mdash;&nbsp;The activity of taxanes in men with castrate-resistant
prostate cancer was initially suggested by multiple phase II studies in which",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" , with or without",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" , was given on either a weekly or every three week schedule. These trials led
to the evaluation of docetaxel in a number of combinations, including a phase III
comparison with",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" , which established the combination of docetaxel plus prednisone as the
standard of care for initial chemotherapy in men with castrate resistant prostate
cancer. This docetaxel plus prednisone regimen has been included in the Cancer Care
Ontario Practice guidelines, which have been endorsed by the American Society of
Clinical Oncology (ASCO).",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h2\">",
" Docetaxel versus mitoxantrone",
" </span>",
" &nbsp;&mdash;&nbsp;In the TAX-327 trial, 1006 men with chemotherapy-naive
metastatic castrate-resistant prostate cancer were randomly assigned to",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" (75",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" every three weeks), docetaxel (30",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" weekly), or",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" (12",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" every three weeks) [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/1\">",
" 1",
" </a>",
" ]. All patients received",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" 5 mg orally twice a day. Patients were continued on maintenance gonadal
androgen suppression, but antiandrogens were discontinued at least four weeks prior
to chemotherapy. Overall survival was the primary endpoint of the trial. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?37/39/38520?
source=see_link&amp;anchor=H4#H4\">",
" \"Secondary endocrine therapies for castration resistant prostate cancer\",
section on 'Continuation of ADT'",
" </a>",
" .)",
" </p>",
" <p>",
" Key results from the trial included the following:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" With an extended follow-up that included death of 86 percent of the
patients, the benefit of the every three week schedule of",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?
source=see_link\">",
" docetaxel",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" has persisted for overall survival (median 19.2 versus 17.8 and 16.3 months
for the weekly docetaxel and",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?
source=see_link\">",
" mitoxantrone",
" </a>",
" regimens, respectively) [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/2\">",
" 2",
" </a>",
" ]. The three-year survival rates were higher in those treated with docetaxel
(18.6 and 16.6 versus 13.5 percent, respectively).",
" </li>",
" <li>",
" In subset analyses, survival benefits were present in those older and
younger than 65 years of age, in those with and without pain at baseline, and in
those whose baseline PSA was greater than or less than the median (115",
" <span class=\"nowrap\">",
" ng/mL).",
" </span>",
" </li>",
" <li>",
" Both",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?
source=see_link\">",
" docetaxel",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" treatment schedules were associated with a higher PSA response rate than
with",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?
source=see_link\">",
" mitoxantrone",
" </a>",
" (45 and 48 versus 32 percent) and a higher pain response rate (35 and 31
versus 22 percent, respectively).",
" </li>",
" <li>",
" Grade 3 or 4 neutropenia was most common with",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?
source=see_link\">",
" docetaxel",
" </a>",
" every three weeks (32 versus 2 and 22 percent). Neutropenic infection was
uncommon with all three regimens (3, 0, and 2 percent, respectively).
Discontinuation of treatment due to adverse effects was uncommon with all three
regimens (11, 16, and 10 percent, respectively).",
" </li>",
" </ul>",
" </p>",
" <p>",
" <a class=\"drug drug_general\" href=\"UTD.htm?33/4/33856?source=see_link\">",
" Dexamethasone",
" </a>",
" (8 mg) was administered 12, 3, and 1 hour prior to infusion with",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" to minimize toxicity. Although some have speculated that the dexamethasone,
rather than the docetaxel, may be responsible for the activity of this combination
[",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/3\">",
" 3",
" </a>",
" ], at least one study found no benefit from dexamethasone alone [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/4\">",
" 4",
" </a>",
" ].",
" </p>",
" <p>",
" These results have established",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" (75",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" every three weeks) plus daily",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" (5 mg twice a day) as the standard of care for men with castrate-resistant
prostate cancer. This regimen has been incorporated into the Cancer Care Ontario
Practice guidelines, which have been endorsed by the American Society of Clinical
Oncology (ASCO) [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/5,6\">",
" 5,6",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H196091783\">",
" <span class=\"h2\">",
" Alternative docetaxel schedules",
" </span>",
" &nbsp;&mdash;&nbsp;For patients who are unlikely to tolerate",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" on an every three week schedule, more frequent administration of docetaxel may
offer a better tolerated alternative. In a phase III trial, patients were randomly
assigned to docetaxel 50",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" every two weeks or to docetaxel 75",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" every three weeks, both given with",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/7\">",
" 7",
" </a>",
" ]. The every two week schedule was associated with an improved time to
treatment failure and overall survival compared with the every three week schedule,
and there was a decrease in the incidence of severe neutropenia (53 versus 36
percent) and febrile neutropenia (14 versus 4 percent).",
" </p>",
" <p>",
" However, weekly use of",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" , as in the TAX-327 trial, was not superior to treatment with",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/1\">",
" 1",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h2\">",
" Other docetaxel combinations",
" </span>",
" &nbsp;&mdash;&nbsp;Several other",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" -based combinations with other cytotoxic agents have shown evidence of
activity in phase II studies, but none of these has an established role. These
include combinations with",
" <a class=\"drug drug_general\" href=\"UTD.htm?0/59/953?source=see_link\">",
" vinorelbine",
" </a>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/8\">",
" 8",
" </a>",
" ],",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/0/40967?source=see_link\">",
" capecitabine",
" </a>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/9\">",
" 9",
" </a>",
" ],",
" <a class=\"drug drug_general\" href=\"UTD.htm?4/27/4536?source=see_link\">",
" epirubicin",
" </a>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/10\">",
" 10",
" </a>",
" ], and",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/61/38873?source=see_link\">",
" carboplatin",
" </a>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/11\">",
" 11",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h1\">",
" SECOND-LINE CHEMOTHERAPY: CABAZITAXEL",
" </span>",
" &nbsp;&mdash;&nbsp;",
" <a class=\"drug drug_general\" href=\"UTD.htm?30/47/31478?source=see_link\">",
" Cabazitaxel",
" </a>",
" is a semisynthetic taxane derivative that was developed for its activity in
patients with resistance to",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" . Cabazitaxel is only indicated for use in combination with",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" for patients who have previously been treated with a docetaxel-containing
regimen [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/12\">",
" 12",
" </a>",
" ].",
" </p>",
" <p>",
" <a class=\"drug drug_general\" href=\"UTD.htm?30/47/31478?source=see_link\">",
" Cabazitaxel",
" </a>",
" is the only chemotherapy agent that has been shown to prolong survival in
patients who have progressed on",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" . In the phase III TROPIC trial, 755 men, all of whom had progressed on
docetaxel, were randomly assigned to oral",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" (10",
" <span class=\"nowrap\">",
" mg/day)",
" </span>",
" plus either cabazitaxel (25",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" as an intravenous infusion every three weeks) or",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" (12",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" every three weeks) [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/13\">",
" 13",
" </a>",
" ]. Premedication to prevent severe hypersensitivity reactions included
antihistamines, steroids, and an H2 antagonist. Antiemetic prophylaxis was
recommended and was given either orally or intravenously as needed.",
" </p>",
" <p>",
" Men treated with",
" <a class=\"drug drug_general\" href=\"UTD.htm?30/47/31478?source=see_link\">",
" cabazitaxel",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" had an increased overall survival compared to those treated with",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" plus prednisone (hazard ratio [HR] 0.70, 95% CI 0.59-0.83, median survival
15.1 versus 12.7 months). Progression-free survival was also significantly
prolonged (2.8 versus 1.4 months, HR 0.74, 95% CI 0.64-0.86). On subset analysis,
the survival benefit was greater in patients who had been most heavily exposed to",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" compared to those with the lowest exposure (HR 0.51 versus HR 0.96 for those
with &gt;900",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" compared to those who had received &lt;225",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" ).",
" </span>",
" </p>",
" <p>",
" The",
" <a class=\"drug drug_general\" href=\"UTD.htm?30/47/31478?source=see_link\">",
" cabazitaxel",
" </a>",
" regimen was significantly more toxic than",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" . Potential treatment-related deaths were more frequent in the 30 days after
last treatment for cabazitaxel compared to mitoxantrone (4.9 versus 2.4 percent).
Grade 3 or greater neutropenia was observed in 82 percent of patients with
cabazitaxel and febrile neutropenia was seen in 8 percent. In addition, diarrhea
was reported in 47 percent of patients and was greater than or equal to grade 3 in
6 percent.",
" </p>",
" <p>",
" Prophylaxis with colony-stimulating factors is indicated to prevent febrile
neutropenia for patients older than 65 years, with extensive prior radiation
therapy, or other high-risk groups. In addition, prophylaxis to prevent infusion
reactions is recommended. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?33/9/33945?
source=see_link\">",
" \"Use of granulocyte colony stimulating factors in patients with
chemotherapy-induced neutropenia\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?42/57/43930?
source=see_link\">",
" \"Infusion reactions to systemic chemotherapy\"",
" </a>",
" .)",
" </p>",
" <p>",
" Additional phase III clinical trials in castrate resistant prostate cancer are
comparing",
" <a class=\"drug drug_general\" href=\"UTD.htm?30/47/31478?source=see_link\">",
" cabazitaxel",
" </a>",
" with",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" as the initial chemotherapy regimen (NCT01308567) and comparing a dose of 20",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" versus 25",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" (NCT01308580) to determine whether comparable efficacy can be achieved with
less myelotoxicity.",
" </p>",
" <p class=\"headingAnchor\" id=\"H15661182\">",
" <span class=\"h1\">",
" OTHER AGENTS",
" </span>",
" &nbsp;&mdash;&nbsp;Several other agents that have been used in the treatment
of advanced prostate cancer do not have an established role in either the first or
second line setting. These may have a role in the management of late stage disease
in selected patients.",
" </p>",
" <p class=\"headingAnchor\" id=\"H66810582\">",
" <span class=\"h2\">",
" Mitoxantrone",
" </span>",
" &nbsp;&mdash;&nbsp;",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" Mitoxantrone",
" </a>",
" is an anthraquinone that is structurally related to the anthracyclines.
Mitoxantrone was the first cytotoxic agent to be approved for the treatment of men
with advanced prostate cancer; the approval was based upon symptom palliation and
not an increase in overall survival in patients who had castrate-resistant
disease.",
" </p>",
" <p>",
" Three randomized trials compared",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" to oral corticosteroids [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/14-16\">",
" 14-16",
" </a>",
" ]. None of the three demonstrated a statistically significant improvement in
overall survival. In the largest of these, 242 men were randomly assigned to either
mitoxantrone plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/49/32528?source=see_link\">",
" hydrocortisone",
" </a>",
" or hydrocortisone alone [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/15\">",
" 15",
" </a>",
" ]. The median overall survival, the trial&rsquo;s primary endpoint, was
approximately 12 months in each group and the median time to disease progression
was short in both groups (3.7 versus 2.3 months). The PSA response was greater with
mitoxantrone compared with hydrocortisone (38 versus 22 percent), and pain control
was better with mitoxantrone.",
" </p>",
" <p>",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" Mitoxantrone",
" </a>",
" retains some activity in patients who have progressed on",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" , although the availability of",
" <a class=\"drug drug_general\" href=\"UTD.htm?30/47/31478?source=see_link\">",
" cabazitaxel",
" </a>",
" and other agents that prolong survival minimize its role in this setting. In
the phase III trial comparing cabazitaxel with mitoxantrone in patients who had
previously been treated with docetaxel, mitoxantrone had a 4 percent objective
response rate and an 18 percent PSA response rate [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/13\">",
" 13",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?10/12/10442?
source=see_link&amp;anchor=H261299639#H261299639\">",
" \"Overview of the treatment of disseminated prostate cancer\", section on
'Castrate resistant disease'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h2\">",
" Estramustine",
" </span>",
" &nbsp;&mdash;&nbsp;",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/4/35909?source=see_link\">",
" Estramustine",
" </a>",
" is a conjugate of an alkylating agent to estradiol. Estramustine has some
activity as a single agent in men with castrate-resistant prostate cancer, which
led to its evaluation in various combination regimens [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/17-21\">",
" 17-21",
" </a>",
" ].",
" </p>",
" <p>",
" However, treatment with",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/4/35909?source=see_link\">",
" estramustine",
" </a>",
" is complicated by an increased risk of both arterial and venous thromboembolic
events [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/22\">",
" 22",
" </a>",
" ]. Although daily",
" <a class=\"drug drug_general\" href=\"UTD.htm?24/7/24698?source=see_link\">",
" aspirin",
" </a>",
" and low dose",
" <a class=\"drug drug_general\" href=\"UTD.htm?27/41/28314?source=see_link\">",
" warfarin",
" </a>",
" have been proposed as prophylaxis, a decrease in thromboembolic complications
using these strategies has not been demonstrated.",
" </p>",
" <p>",
" Although the combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/4/35909?source=see_link\">",
" estramustine",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" improved overall survival in a phase III trial compared with",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?source=see_link\">",
" prednisone",
" </a>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/23\">",
" 23",
" </a>",
" ], this combination was associated with excessive toxicity and does not have
an established role.",
" </p>",
" <p class=\"headingAnchor\" id=\"H15661271\">",
" <span class=\"h2\">",
" Paclitaxel",
" </span>",
" &nbsp;&mdash;&nbsp;The taxane",
" <a class=\"drug drug_general\" href=\"UTD.htm?16/58/17320?source=see_link\">",
" paclitaxel",
" </a>",
" has been less extensively evaluated than",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" in men with castrate-resistant prostate cancer. Paclitaxel does not have an
established role in these patients, but appears to have activity that is schedule
dependent.",
" </p>",
" <p>",
" The efficacy of weekly therapy was illustrated in a study of 43 men with
castrate-resistant prostate cancer who received",
" <a class=\"drug drug_general\" href=\"UTD.htm?16/58/17320?source=see_link\">",
" paclitaxel",
" </a>",
" (80",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" over one hour) weekly for six of every eight weeks [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/24\">",
" 24",
" </a>",
" ]. A PSA response was noted in 36 percent, and 5 of 16 men with measurable
disease had a partial response. In contrast, another study using a 24 hour infusion
of paclitaxel showed only minimal activity [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/25\">",
" 25",
" </a>",
" ].",
" </p>",
" <p>",
" <a class=\"drug drug_general\" href=\"UTD.htm?16/58/17320?source=see_link\">",
" Paclitaxel",
" </a>",
" has been combined with",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/4/35909?source=see_link\">",
" estramustine",
" </a>",
" in several phase II studies [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/26,27\">",
" 26,27",
" </a>",
" ]. Although these regimens have some activity and have been well tolerated,
the role of estramustine has been called into question by the results of phase III
trials [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/23\">",
" 23",
" </a>",
" ]. Attempts to augment the activity of the paclitaxel plus estramustine
combination have included the addition of a third agent such as",
" <a class=\"drug drug_general\" href=\"UTD.htm?29/57/30617?source=see_link\">",
" etoposide",
" </a>",
" or",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/61/38873?source=see_link\">",
" carboplatin",
" </a>",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/28\">",
" 28",
" </a>",
" ]. Randomized phase III comparisons have not been conducted and would be
required to determine whether such combinations are beneficial.",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h2\">",
" Miscellaneous agents",
" </span>",
" &nbsp;&mdash;&nbsp;A number of older drugs were evaluated and showed evidence
of at least limited activity. These included antimetabolites (",
" <a class=\"drug drug_general\" href=\"UTD.htm?32/32/33280?source=see_link\">",
" fluorouracil",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?31/1/31769?source=see_link\">",
" gemcitabine",
" </a>",
" ),",
" <a class=\"drug drug_general\" href=\"UTD.htm?9/20/9546?source=see_link\">",
" cyclophosphamide",
" </a>",
" , platinum analogs,",
" <a class=\"drug drug_general\" href=\"UTD.htm?10/11/10423?source=see_link\">",
" ixabepilone",
" </a>",
" , and topoisomerase I inhibitors alone or in various combinations [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/29-38\">",
" 29-38",
" </a>",
" ]. Objective response rates were generally 10 to 20 percent or less, and the
use of these agents has been supplanted by the development of",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?source=see_link\">",
" docetaxel",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?source=see_link\">",
" mitoxantrone",
" </a>",
" , and",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/4/35909?source=see_link\">",
" estramustine",
" </a>",
" .",
" </p>",
" <p class=\"headingAnchor\" id=\"H19\">",
" <span class=\"h1\">",
" PROSTATE CANCER WITH LOW PSA PRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Some men with aggressive metastatic prostate cancer have
low serum PSA values [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/39-41\">",
" 39-41",
" </a>",
" ]. These patients are more likely to have visceral and osteolytic metastases
rather than osteoblastic bone lesions. In this setting, serum PSA cannot be used as
a marker to assess the response to treatment.",
" </p>",
" <p>",
" There are no randomized trials to guide management of patients with castrate-
resistant prostate cancer and a low serum PSA. Our approach to treatment in these
patients varies depending upon the histology:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Patients with tumors that contain neuroendocrine (small cell) features are
relatively sensitive to chemotherapy regimens that are used for small cell cancer
involving the lung (eg,",
" <span class=\"nowrap\">",
" platinum/",
" <a class=\"drug drug_general\" href=\"UTD.htm?29/57/30617?
source=see_link\">",
" etoposide",
" </a>",
" </span>",
" combinations), with response rates of over 50 percent. Nevertheless, the
optimal treatment regimen is unknown, and clinical studies are sparse. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?6/39/6778?
source=see_link\">",
" \"First-line chemotherapy for patients with extensive stage small cell lung
cancer\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/31/3578?
source=see_link&amp;anchor=H6#H6\">",
" \"Extrapulmonary small cell cancer\", section on 'Prostate ESCC'",
" </a>",
" .)",
" </li>",
" <li>",
" Patients with poorly differentiated adenocarcinoma tend to have a clinically
aggressive course. Although a combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?16/58/17320?
source=see_link\">",
" paclitaxel",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/4/35909?
source=see_link\">",
" estramustine",
" </a>",
" , and",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/61/38873?
source=see_link\">",
" carboplatin",
" </a>",
" may be useful in those without neuroendocrine features [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6280/abstract/28,42\">",
" 28,42",
" </a>",
" ], there are no data demonstrating that this is more effective than",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?
source=see_link\">",
" docetaxel",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" .",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" <span class=\"h1\">",
" INFORMATION FOR PATIENTS",
" </span>",
" &nbsp;&mdash;&nbsp;UpToDate offers two types of patient education materials,
&ldquo;The Basics&rdquo; and &ldquo;Beyond the Basics.&rdquo; The Basics patient
education pieces are written in plain language, at the 5",
" ^{",
" th",
"}",
" to 6",
" ^{",
" th",
"}",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" ^{",
" th",
"}",
" to 12",
" ^{",
" th",
"}",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
&ldquo;patient info&rdquo; and the keyword(s) of interest.)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Beyond the Basics topics (see",
" <a class=\"medical medical_patient\" href=\"UTD.htm?41/41/42643?
source=see_link\">",
" \"Patient information: Treatment for advanced prostate cancer (Beyond the
Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H21\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" For chemotherapy-naive men with castrate-resistant prostate cancer without
neuroendocrine (small cell) who are candidates for cytotoxic chemotherapy, we
recommend",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?
source=see_link\">",
" docetaxel",
" </a>",
" (75",
" <span class=\"nowrap\">",
" mg/m",
" ^{",
" 2",
"}",
" </span>",
" every three weeks) plus oral",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" (5 mg twice a day) rather than other chemotherapy regimens (",
" <a class=\"grade\" href=\"._grade_2?title=Grade 1B\">",
" Grade 1B",
" </a>",
" ). This docetaxel plus prednisone regimen has been included in the Cancer
Care Ontario Practice guidelines, which have been endorsed by the American Society
of Clinical Oncology (ASCO). (See",
" <a class=\"local\" href=\"#H9\">",
" 'Docetaxel versus mitoxantrone'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" This schedule of",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?
source=see_link\">",
" docetaxel",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" significantly increased survival compared to",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?
source=see_link\">",
" mitoxantrone",
" </a>",
" plus prednisone in the TAX-327 trial. Giving docetaxel on a two weekly
schedule may offer a better tolerated alternative, but the improvement in survival
with a weekly schedule of docetaxel was not statistically significant compared with
mitoxantrone. (See",
" <a class=\"local\" href=\"#H9\">",
" 'Docetaxel versus mitoxantrone'",
" </a>",
" above.)",
" </li>",
" <li>",
" Gonadal androgen suppression but not antiandrogens should be continued
during chemotherapy. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?37/39/38520?
source=see_link&amp;anchor=H4#H4\">",
" \"Secondary endocrine therapies for castration resistant prostate cancer\",
section on 'Continuation of ADT'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" For patients with castrate resistant prostate cancer who have progressed on
treatment with",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?
source=see_link\">",
" docetaxel",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" , there are a number of treatment regimens that have been shown to prolong
overall survival (",
" <a class=\"graphic graphic_table graphicRef85716 \" href=\"UTD.htm?
17/56/18317\">",
" table 1",
" </a>",
" ). For those who are candidates for second-line cytotoxic chemotherapy, we
recommend",
" <a class=\"drug drug_general\" href=\"UTD.htm?30/47/31478?
source=see_link\">",
" cabazitaxel",
" </a>",
" (",
" <a class=\"grade\" href=\"._grade_2?title=Grade 1B\">",
" Grade 1B",
" </a>",
" ). Cabazitaxel plus prednisone significantly increased overall survival
compared with",
" <a class=\"drug drug_general\" href=\"UTD.htm?36/31/37368?
source=see_link\">",
" mitoxantrone",
" </a>",
" plus prednisone. (See",
" <a class=\"local\" href=\"#H12\">",
" 'Second-line chemotherapy: cabazitaxel'",
" </a>",
" above.)",
" </li>",
" <li>",
" Patients with castrate-resistant prostate cancer and a low serum PSA are
more likely to have aggressive disease, including the presence of visceral
metastases rather than bone metastases. There are no randomized trials to guide
therapy in this setting:",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" For patients with poorly differentiated adenocarcinoma without
neuroendocrine features, we suggest a combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?40/59/41913?
source=see_link\">",
" docetaxel",
" </a>",
" plus",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/43/38585?
source=see_link\">",
" prednisone",
" </a>",
" &nbsp;(",
" <a class=\"grade\" href=\"._grade_6?title=Grade 2C\">",
" Grade 2C",
" </a>",
" ). A combination of",
" <a class=\"drug drug_general\" href=\"UTD.htm?16/58/17320?
source=see_link\">",
" paclitaxel",
" </a>",
" ,",
" <a class=\"drug drug_general\" href=\"UTD.htm?35/4/35909?
source=see_link\">",
" estramustine",
" </a>",
" , and",
" <a class=\"drug drug_general\" href=\"UTD.htm?37/61/38873?
source=see_link\">",
" carboplatin",
" </a>",
" may be an alternative. (See",
" <a class=\"local\" href=\"#H19\">",
" 'Prostate cancer with low PSA production'",
" </a>",
" above.)",
" </li>",
" <li>",
" Those patients whose tumors have a substantial component with neuroendocrine
features may benefit from treatment with a chemotherapy regimen similar to that
used for patients with small cell lung cancer. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?6/39/6778?
source=see_link\">",
" \"First-line chemotherapy for patients with extensive stage small cell lung
cancer\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?3/31/3578?
source=see_link&amp;anchor=H6#H6\">",
" \"Extrapulmonary small cell cancer\", section on 'Prostate ESCC'",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/1\">",
" Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;
351:1502.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/2\">",
" Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the
TAX 327 study. J Clin Oncol 2008; 26:242.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/3\">",
" Haines IE, Stanley RM. Perspective on \"Chemotherapy for advanced prostate
cancer: 25 years later\": is it a mirage or an oasis? J Clin Oncol 2008; 26:4049.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/4\">",
" Weitzman AL, Shelton G, Zuech N, et al. Dexamethasone does not significantly
contribute to the response rate of docetaxel and estramustine in androgen
independent prostate cancer. J Urol 2000; 163:834.",
" </a>",
" </li>",
" <li>",
" Winquist E, Waldron T, Berry S, et al. Nonhormonal systemic therapy in men
with hormone-refractory prostate cancer: A Clinical Practice Guideline, 2005
www.cancercare.on.ca/pdf/pebc3-15s.pdf (Accessed on April 18, 2011).",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/6\">",
" Basch EM, Somerfield MR, Beer TM, et al. American Society of Clinical
Oncology endorsement of the Cancer Care Ontario Practice Guideline on nonhormonal
therapy for men with metastatic hormone-refractory (castration-resistant) prostate
cancer. J Clin Oncol 2007; 25:5313.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/7\">",
" Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, et al. 2-Weekly versus 3-
weekly docetaxel to treat castration-resistant advanced prostate cancer: a
randomised, phase 3 trial. Lancet Oncol 2013; 14:117.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/8\">",
" Hahn NM, Marsh S, Fisher W, et al. Hoosier Oncology Group randomized phase
II study of docetaxel, vinorelbine, and estramustine in combination in hormone-
refractory prostate cancer with pharmacogenetic survival analysis. Clin Cancer Res
2006; 12:6094.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/9\">",
" Ferrero JM, Chamorey E, Oudard S, et al. Phase II trial evaluating a
docetaxel-capecitabine combination as treatment for hormone-refractory prostate
cancer. Cancer 2006; 107:738.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/10\">",
" Petrioli R, Paolelli L, Francini E, et al. Weekly docetaxel and epirubicin
in treatment of advanced hormone-refractory prostate cancer. Urology 2007;
69:142.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/11\">",
" Ross RW, Beer TM, Jacobus S, et al. A phase 2 study of carboplatin plus
docetaxel in men with metastatic hormone-refractory prostate cancer who are
refractory to docetaxel. Cancer 2008; 112:521.",
" </a>",
" </li>",
" <li>",
" US Food and Drug Administration package insert
file://www.accessdata.fda.gov/drugsatfda_docs/label/2010/201023lbl.pdf (Accessed on
April 18, 2011).",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/13\">",
" de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or
mitoxantrone for metastatic castration-resistant prostate cancer progressing after
docetaxel treatment: a randomised open-label trial. Lancet 2010; 376:1147.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/14\">",
" Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus
prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a
Canadian randomized trial with palliative end points. J Clin Oncol 1996; 14:1756.",
" </a>",
" </li>",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/8/6280/abstract/15\">",
" Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without
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" </a>",
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" INTRODUCTION",
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var title_f6_8_6281="Clinical manifestations, diagnosis, and natural history of
alpha-1 antitrypsin deficiency";
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" Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin
deficiency",
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" Author",
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6/8/6281/contributors\">",
" James K Stoller, MS, MD",
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" Section Editor",
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6/8/6281/contributors\">",
" Peter J Barnes, DM, DSc, FRCP, FRS",
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" <br/>",
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href=\"UTD.htm?6/8/6281/contributors\">",
" Deputy Editor",
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6/8/6281/contributors\">",
" Helen Hollingsworth, MD",
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" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" &nbsp;&mdash;&nbsp;Alpha-1 antitrypsin (AAT) deficiency is a clinically under-
recognized inherited disorder affecting the lung, liver, and rarely, skin. The
characteristics of the pulmonary manifestations of this disorder will be reviewed
here [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/1-4\">",
" 1-4",
" </a>",
" ]. Extrapulmonary disease and therapy are discussed separately. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/45/18136?
source=see_link\">",
" \"Extrapulmonary manifestations of alpha-1 antitrypsin deficiency\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?15/62/16361?
source=see_link\">",
" \"Treatment of alpha-1 antitrypsin deficiency\"",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H2\">",
" <span class=\"h1\">",
" AAT PHENOTYPES",
" </span>",
" &nbsp;&mdash;&nbsp;AAT is a protease inhibitor (encoded by the gene PI, MIM
+107400) of the proteolytic enzyme elastase. It is part of a larger family of
structurally unique serine protease inhibitors, referred to as serpins, which have
been implicated in the pathogenesis of neurodegenerative diseases, angioedema, and
coagulation abnormalities [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/1,5\">",
" 1,5",
" </a>",
" ]. At least 100 alleles of AAT have been identified and given a letter code
based upon electrophoretic mobility. They can be categorized into four basic
groups:",
" </p>",
" <p class=\"headingAnchor\" id=\"H3\">",
" <span class=\"h2\">",
" Normal",
" </span>",
" &nbsp;&mdash;&nbsp;Normal alleles are associated with normal levels of AAT and
normal function. The family of normal alleles is referred to as M and the normal
phenotype is MM.",
" </p>",
" <p class=\"headingAnchor\" id=\"H4\">",
" <span class=\"h2\">",
" Deficient",
" </span>",
" &nbsp;&mdash;&nbsp;Deficient alleles are associated with plasma AAT levels
less than 35 percent of the average normal level. The most common deficient allele
associated with emphysema is the Z allele, which is carried by approximately 2 to 3
percent of the Caucasian population in the United States.",
" </p>",
" <p class=\"headingAnchor\" id=\"H5\">",
" <span class=\"h2\">",
" Null",
" </span>",
" &nbsp;&mdash;&nbsp;Null alleles lead to no detectable AAT protein in the
plasma. Individuals with the null phenotype are the least common and are at risk
for the most severe form of associated lung disease.",
" </p>",
" <p class=\"headingAnchor\" id=\"H6\">",
" <span class=\"h2\">",
" Dysfunctional",
" </span>",
" &nbsp;&mdash;&nbsp;Dysfunctional alleles produce a normal quantity of AAT
protein but the protein does not function properly (eg, PI*F).",
" </p>",
" <p>",
" Population studies suggest a minimum plasma threshold of 11 micromol per L
(corresponding to 50 to 80 mg per dL, depending on the assay used), below which
there is insufficient AAT to protect the lung, leading to an increased risk of
developing emphysema. Most patients below this threshold level have the PI*Z
phenotype (ie, homozygous PI*ZZ) (",
" <a class=\"graphic graphic_table graphicRef57264 \" href=\"UTD.htm?
3/4/3148\">",
" table 1",
" </a>",
" )&nbsp;[",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/6\">",
" 6",
" </a>",
" ].",
" </p>",
" <p>",
" The American Thoracic Society (ATS) and European Respiratory Society (ERS)
statement on the diagnosis and management of AAT deficiency, as well as other ATS
guidelines, can be accessed through the ATS web site at",
" <a class=\"external\" href=\"file://www.thoracic.org/statements\">",
" www.thoracic.org/statements",
" </a>",
" .",
" </p>",
" <p class=\"headingAnchor\" id=\"H7\">",
" <span class=\"h1\">",
" EPIDEMIOLOGY",
" </span>",
" &nbsp;&mdash;&nbsp;Although AAT deficiency is commonly considered to be rare,
estimates that 80,000 to 100,000 individuals in the United States have severe
deficiency of AAT suggest that the disease is under-recognized [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/7,8\">",
" 7,8",
" </a>",
" ]. The prevalence of AAT varies considerably from one country to another;
however, it is estimated that more than 3 million people worldwide have allele
combinations associated with severe deficiency [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/9,10\">",
" 9,10",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H8\">",
" <span class=\"h2\">",
" Prevalence",
" </span>",
" &nbsp;&mdash;&nbsp;Two lines of evidence support prevalence estimates
indicating that AAT deficiency is approximately as common as cystic fibrosis:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" One study evaluated a sample of 965 patients with chronic obstructive
pulmonary disease (COPD); severe deficiency of AAT was found in 2 to 3 percent [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/11\">",
" 11",
" </a>",
" ]. Extrapolating to the United States population of 2.1 million individuals
with emphysema (based on the National Health Interview Survey [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/12\">",
" 12",
" </a>",
" ]), 40,000 to 60,000 Americans would be expected to have emphysema caused by
AAT deficiency.",
" </li>",
" <li>",
" Direct population screening studies indicate that the prevalence of
individuals with the PI*Z phenotype and resultant severe deficiency of AAT ranges
from one in 1575 to one in 5097 individuals [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/13-16\">",
" 13-16",
" </a>",
" ]. Based upon the United States population of approximately 310 million,
80,000 to 100,000 severely AAT deficient individuals would be expected. This
estimate includes both symptomatic and asymptomatic patients.",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H9\">",
" <span class=\"h2\">",
" Unrecognized deficiency",
" </span>",
" &nbsp;&mdash;&nbsp;Several studies indicate that AAT deficiency is far less
familiar to many clinicians than its prevalence would suggest. Investigators in one
report, for example, estimated that there were 700 PI*ZZ individuals in St. Louis,
based upon sampling of 20,000 blood specimens submitted to the St. Louis blood
bank; only 28 of these individuals (4 percent) had been identified [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/15\">",
" 15",
" </a>",
" ]. Unrecognized individuals with severe deficiency of AAT probably comprise
two separate groups: those with no clinical manifestations despite severe
deficiency; and those with disease in whom the underlying AAT deficiency has been
unrecognized. The relative proportion of these two groups remains unknown.",
" </p>",
" <p>",
" Under-recognition of AAT deficiency has also been demonstrated [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/7,8,17\">",
" 7,8,17",
" </a>",
" ]. A poll of 304 individuals with severe deficiency of AAT indicated an
average delay of 7.2 years between the first onset of symptoms and the diagnosis of
AAT deficiency. Furthermore, 43 percent of respondents reported seeing at least
three clinicians and 12 percent reported seeing between 6 and 10 clinicians before
the diagnosis of AAT deficiency was first made. Two more recent surveys
demonstrated that the delay between the first symptom and recognition of AAT
deficiency had not decreased [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/7,8\">",
" 7,8",
" </a>",
" ], indicating that under-recognition persists despite extensive educational
efforts and the publication of evidence-based guidelines for diagnosis and
management of AAT deficiency [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/4\">",
" 4",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H10\">",
" <span class=\"h1\">",
" CLINICAL MANIFESTATIONS",
" </span>",
" &nbsp;&mdash;&nbsp;The main clinical manifestations relate to three separate
organs: the lung, the liver, and much less often the skin. Sporadic reports
indicate other clinical conditions also may accompany AAT deficiency. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/45/18136?
source=see_link\">",
" \"Extrapulmonary manifestations of alpha-1 antitrypsin deficiency\"",
" </a>",
" .)",
" </p>",
" <p>",
" In the lung, severe deficiency of AAT predisposes to chronic obstructive
pulmonary disease, especially",
" <strong>",
" panacinar emphysema",
" </strong>",
" (",
" <a class=\"graphic graphic_diagnosticimage graphicRef62580 graphicRef79789 \"
href=\"UTD.htm?21/5/21591\">",
" image 1A-B",
" </a>",
" )&nbsp;[",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/18,19\">",
" 18,19",
" </a>",
" ]. Some series also report an association of AAT deficiency with
bronchiectasis",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" asthma, but these relationships have not been as firmly established [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/20\">",
" 20",
" </a>",
" ].",
" </p>",
" <p>",
" Emphysema in AAT deficiency is thought to result from an imbalance between
neutrophil elastase in the lung, which destroys elastin, and the elastase inhibitor
AAT, which protects against proteolytic degradation of elastin.",
" </p>",
" <p>",
" The pathogenesis of the liver disease is quite different. Only those
phenotypes associated with pathologic polymerization of AAT within the endoplasmic
reticulum of hepatocytes produce disease [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/21-23\">",
" 21-23",
" </a>",
" ]. Most patients are homozygous for PI*Z; liver disease does not occur in null
homozygotes who have severe AAT deficiency but no intra-hepatocytic accumulation.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/45/18136?
source=see_link&amp;anchor=H2#H2\">",
" \"Extrapulmonary manifestations of alpha-1 antitrypsin deficiency\", section
on 'Hepatic disease'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"H11\">",
" <span class=\"h2\">",
" Risk factors for lung disease",
" </span>",
" &nbsp;&mdash;&nbsp;Individuals with phenotypes associated with plasma AAT
levels below the protective threshold of 11",
" <span class=\"nowrap\">",
" micromol/L",
" </span>",
" (~57",
" <span class=\"nowrap\">",
" mg/dL",
" </span>",
" using nephelometry and 80",
" <span class=\"nowrap\">",
" mg/dL",
" </span>",
" by radial immunodiffusion) are considered to have severe AAT deficiency and
are at risk for emphysema [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/4,24\">",
" 4,24",
" </a>",
" ]. The normal plasma concentration of AAT ranges from 20 to 48 micromol",
" <span class=\"nowrap\">",
" /L",
" </span>",
" (80 to 220",
" <span class=\"nowrap\">",
" mg/dL",
" </span>",
" using nephelometry or 150 to 350",
" <span class=\"nowrap\">",
" mg/dL",
" </span>",
" by radial immunodiffusion) (",
" <a class=\"graphic graphic_table graphicRef57264 \" href=\"UTD.htm?
3/4/3148\">",
" table 1",
" </a>",
" ).",
" </p>",
" <p>",
" Many phenotypes can be associated with severe AAT deficiency, including
PI*Null variants, some heterozygous PI*SZ individuals, and PI*M[Heerlen] [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/6,25\">",
" 6,25",
" </a>",
" ]. However, the vast majority of patients are PI*ZZ homozygotes. Plasma AAT
levels in these patients cluster tightly around 5 to 6",
" <span class=\"nowrap\">",
" micromol/L",
" </span>",
" (30 to 40",
" <span class=\"nowrap\">",
" mg/dL).",
" </span>",
" </p>",
" <p>",
" Severe deficiency of AAT poses a strong risk factor for early-onset emphysema,
but not every severely deficient individual is destined to develop emphysema. Risk
factors include cigarette smoking, dusty occupational exposure, a parental history
of COPD, and a personal history of asthma, chronic bronchitis, or pneumonia [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/26,27\">",
" 26,27",
" </a>",
" ].",
" </p>",
" <p>",
" Cigarette smoking increases the risk of developing fixed airflow obstruction
and can markedly accelerate the onset of dyspnea by as much as 19 years. In three
studies, for example, the age at onset of dyspnea was 48 to 54 years in nonsmokers
versus 32 to 40 years in smokers [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/28-30\">",
" 28-30",
" </a>",
" ]. In individuals with the PI*SZ phenotype, cigarette smoking is a
particularly important risk factor for the development of COPD, which rarely occurs
in nonsmokers with this phenotype [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/31\">",
" 31",
" </a>",
" ].",
" </p>",
" <p>",
" Whether non-smoking PI*MZ heterozygotes are at increased risk of emphysema
remains controversial, with available studies showing discordant results:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" In supportive studies, a comparison between individuals in the Lung Health
Study with either rapid or slow decline in forced expiratory volume in one second
(FEV",
" _{",
" 1",
"}",
" ) showed that the MZ phenotype was associated with rapid decline (odds ratio
2.8, p = 0.03) [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/32\">",
" 32",
" </a>",
" ]. Also, a longitudinal study showed a slightly greater annual decrease in
FEV",
" _{",
" 1",
"}",
" in individuals with the MZ genotype compared with those who have the MM
genotype (25 versus 21",
" <span class=\"nowrap\">",
" mL/yr,",
" </span>",
" p = 0.048) [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/33\">",
" 33",
" </a>",
" ]. The odds ratio for developing airflow obstruction was 1.3 in the MZ
heterozygotes compared with normal MM homozygotes. The increase in COPD risk among
PI*MZ heterozygotes may be limited to those with a symptomatic PI*ZZ first-degree
relative [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/34\">",
" 34",
" </a>",
" ].",
" </li>",
" <li>",
" In an analysis of data from case-control and a multicenter family studies,
individuals with PI*MZ, compared to those with PI*MM, had a slightly lower ratios
for",
" <span class=\"nowrap\">",
" FEV",
" _{",
" 1",
"}",
" /forced",
" </span>",
" vital capacity or",
" <span class=\"nowrap\">",
" FEV",
" _{",
" 1",
"}",
" /vital",
" </span>",
" capacity, but no difference in FEV",
" _{",
" 1",
"}",
" [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/35\">",
" 35",
" </a>",
" ].",
" </li>",
" <li>",
" In contrast, results from a population study of PI*MZ heterozygotes from the
Tucson Epidemiologic Study of Airways Obstructive Diseases failed to show any
increased risk of developing airflow obstruction in these MZ individuals [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/36\">",
" 36",
" </a>",
" ]. Also, a meta-analysis highlights the inconsistency of results from
available studies [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/37\">",
" 37",
" </a>",
" ], with studies using categorical outcomes generally showing an increased
risk and those using continuous measures (eg, FEV",
" _{",
" 1",
"}",
" ) not showing an excess risk in PI*MZ heterozygotes. Relatively few of the
available studies adjusted for smoking status and those that did tended to show a
smaller risk (odds ratio 1.61, 95% CI 0.92 &ndash; 2.81).",
" </li>",
" </ul>",
" </p>",
" <p>",
" The precise role of occupational exposures in accelerating the loss of lung
function in AAT deficiency is also incompletely understood. One study found a link
between self-reported exposure to mineral dust and reduced lung function in PI*ZZ
patients [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/38\">",
" 38",
" </a>",
" ], while a second trial suggested that agricultural work and the use of
domiciliary kerosene are also independently associated with a more rapid loss of
lung function [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/39\">",
" 39",
" </a>",
" ]. Among New York City Fire Department rescue workers who were exposed to
respirable particulates and combustion by-products following the World Trade Center
collapse, those with even mild or moderate deficiency of AAT (eg, PI*MZ, PI*SZ, and
PI*MS) had a more rapid decline in FEV",
" _{",
" 1",
"}",
" over the next four years than those with normal AAT levels [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/40\">",
" 40",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H12\">",
" <span class=\"h2\">",
" Clinical presentation of lung disease",
" </span>",
" &nbsp;&mdash;&nbsp;The clinical presentation of emphysema due to AAT
deficiency has many features in common with usual COPD. Dyspnea is the most common
symptom, and many patients report cough, phlegm production, and wheezing, either
chronically or with upper respiratory tract infections [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/30,41-43\">",
" 30,41-43",
" </a>",
" ]. Bronchodilator responsiveness (defined as a post-bronchodilator FEV",
" _{",
" 1",
"}",
" rise of 200 mL and 12 percent) is common in both groups. There are, however,
two features of emphysema associated with severe deficiency of AAT that may be
distinctive and should lead to suspicion of the diagnosis (",
" <a class=\"graphic graphic_table graphicRef61623 \" href=\"UTD.htm?
3/7/3195\">",
" table 2",
" </a>",
" ):",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" The onset of emphysema in AAT-deficient individuals may be earlier than that
in non-AAT-deficient individuals, who usually present in the sixth and seventh
decades of life. In the National Heart, Lung, and Blood Institute-sponsored
Registry for Patients with Severe Deficiency of Alpha-1 Antitrypsin, for example,
the mean (&plusmn; SD) FEV",
" _{",
" 1",
"}",
" in 1129 participants was 43 &plusmn; 30 percent of predicted and their mean
age was 46 &plusmn; 11 years [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/42\">",
" 42",
" </a>",
" ]. Similarly, an earlier series of 246 PI*ZZ adults found that chronic
obstructive pulmonary disease was present in 74.8 percent of the participants,
whose median age was approximately 52 years [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/28\">",
" 28",
" </a>",
" ].",
" </li>",
" <li>",
" Emphysema associated with AAT deficiency often shows a characteristic chest
radiographic pattern, in which bullous changes are more prominent at the lung bases
than at the apices (",
" <a class=\"graphic graphic_diagnosticimage graphicRef62580
graphicRef79789 \" href=\"UTD.htm?21/5/21591\">",
" image 1A-B",
" </a>",
" ). The prevalence of this pattern of \"basilar hyperlucency\" varies among
series [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/3,43\">",
" 3,43",
" </a>",
" ]. The largest reported series of 165 PI*Z homozygotes examined with plain
chest radiographs found that 140 (85 percent) had some radiographic features of
emphysema. Virtually all of these patients had emphysematous changes that included
the lung bases, and 24 percent had emphysematous changes that were limited to the
lung bases. More recent imaging studies have used computed tomography [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/44,45\">",
" 44,45",
" </a>",
" ]. In one study of PI*ZZ individuals, emphysematous abnormalities were most
prominent at the bases in 64 percent of patients and at the apices in 36 percent
[",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/44\">",
" 44",
" </a>",
" ]. In another case series examining CT scan findings, emphysematous changes
were less prominent overall and more likely to be upper lung zone predominant in
PISZ individuals, than PI*Z homozygotes, despite comparable physiologic impairment
[",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/46\">",
" 46",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Severe deficiency of AAT has also been associated with",
" <strong>",
" bronchiectasis",
" </strong>",
" . In one study, for example, bronchiectasis was present in 11.3 percent of 246
PI*Z homozygotes [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/28\">",
" 28",
" </a>",
" ]. The estimated prevalence in other reports has varied widely from 2 to 43
percent [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/47\">",
" 47",
" </a>",
" ]. The relationship between AAT deficiency and bronchiectasis remains
incompletely understood, and the mechanism by which the former could produce the
latter is debated. Bronchiectasis seems to occur most commonly in lobes with higher
emphysema scores [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/47\">",
" 47",
" </a>",
" ]. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?12/10/12458?
source=see_link\">",
" \"Clinical manifestations and diagnosis of bronchiectasis in adults\"",
" </a>",
" .)",
" </p>",
" <p>",
" There is an uncertain relationship between severe AAT deficiency and",
" <strong>",
" asthma",
" </strong>",
" . Studies have not shown an increased prevalence of AAT deficiency among
asthmatics. However, in a large cohort study of over 1000 patients with severe AAT
deficiency, 21 percent of patients met diagnostic criteria for asthma [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/48\">",
" 48",
" </a>",
" ]. The presence of asthma was not independently associated with an accelerated
decline in pulmonary function, and the results of augmentation therapy appear to be
similar for asthmatics and nonasthmatic patients with severe AAT deficiency [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/48\">",
" 48",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H13\">",
" <span class=\"h1\">",
" DIAGNOSIS",
" </span>",
" &nbsp;&mdash;&nbsp;The imperative to identify affected individuals becomes
stronger with the availability of specific therapy for AAT deficiency. Patients
with persistent airflow obstruction on spirometry should be tested. Additional
features that should lead clinicians to test for severe AAT deficiency include (",
" <a class=\"graphic graphic_table graphicRef61623 \" href=\"UTD.htm?
3/7/3195\">",
" table 2",
" </a>",
" )&nbsp;[",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/4\">",
" 4",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bulletCompact-block\">",
" <li>",
" Emphysema in a young individual (eg, age &le;45 years)",
" </li>",
" <li>",
" Emphysema in a nonsmoker or minimal smoker",
" </li>",
" <li>",
" Emphysema characterized by predominant basilar changes on the chest
radiograph",
" </li>",
" <li>",
" A family history of emphysema",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" liver disease",
" </li>",
" <li>",
" Clinical findings or history of panniculitis",
" </li>",
" <li>",
" Clinical findings or history of unexplained chronic liver disease",
" </li>",
" </ul>",
" </p>",
" <p>",
" The diagnosis of severe AAT deficiency is confirmed by demonstrating a serum
level below 11",
" <span class=\"nowrap\">",
" micromol/L",
" </span>",
" (50 to 80",
" <span class=\"nowrap\">",
" mg/dL)",
" </span>",
" in combination with a severe deficient genotype, generally determined by
isoelectric focusing or by polymerase chain reaction assays for the commonest
deficient alleles, ie, S and Z. Genotyping is generally performed on a blood sample
using polymerase chain reaction technology or melting curve analysis [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/49,50\">",
" 49,50",
" </a>",
" ]. If the AAT serum level is greater than 20",
" <span class=\"nowrap\">",
" micromol/L",
" </span>",
" (80",
" <span class=\"nowrap\">",
" mg/dL),",
" </span>",
" it is unlikely that the patient has clinically important AAT deficiency. On
the other hand, if one is evaluating for the presence of particular mutations,
genotyping is necessary to identify heterozygotes and mutations that have
incomplete penetrance [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/50\">",
" 50",
" </a>",
" ].",
" </p>",
" <p>",
" Rarely (&lt;4 percent of tests), the results of the AAT serum level and
genotyping are discordant. In this case, protein phenotype analysis is performed by
isoelectric focusing electrophoresis (available in specialty laboratories) to
identify alleles with abnormal protein migration patterns.",
" </p>",
" <p class=\"headingAnchor\" id=\"H14\">",
" <span class=\"h1\">",
" NATURAL HISTORY",
" </span>",
" &nbsp;&mdash;&nbsp;Current understanding of the natural history of AAT
deficiency is patchy, with some aspects being reasonably clear and others still
murky [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/4\">",
" 4",
" </a>",
" ].",
" </p>",
" <p class=\"headingAnchor\" id=\"H15\">",
" <span class=\"h2\">",
" First two decades of life",
" </span>",
" &nbsp;&mdash;&nbsp;Within the first two decades of life, liver dysfunction is
the major threat to the health of affected individuals, and pulmonary dysfunction
is not a major concern. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/45/18136?
source=see_link&amp;anchor=H2#H2\">",
" \"Extrapulmonary manifestations of alpha-1 antitrypsin deficiency\", section
on 'Hepatic disease'",
" </a>",
" .)",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" In a follow-up study of 15 adolescents identified as PI*ZZ homozygotes at
birth in Oregon, all had normal post-bronchodilator spirometry measurements [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/51\">",
" 51",
" </a>",
" ]. In support of the benefit of neonatal screening, these subjects had a
lower rate of current smoking or of trying smoking than an age-matched cohort.",
" </li>",
" <li>",
" Similar findings were noted in a study of 103 PI*ZZ adolescents (aged 16
years) previously found to have AAT deficiency during neonatal screening in Sweden
[",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/52\">",
" 52",
" </a>",
" ]. Compared with an age-matched cohort, the lung function of AAT-deficient
adolescents was preserved, and very few (3 percent) of these individuals had ever
started smoking.",
" </li>",
" <li>",
" A study of PI*ZZ subjects who were detected by screening at birth,
demonstrated normal spirometry at age 30 years [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/53\">",
" 53",
" </a>",
" ]. Also, high resolution chest CT scans in these newborn-screened AAT
deficient individuals at age 32 failed to show evidence of emphysema [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/54\">",
" 54",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p class=\"headingAnchor\" id=\"H16\">",
" <span class=\"h2\">",
" Later decades",
" </span>",
" &nbsp;&mdash;&nbsp;Beyond the first two to three decades of life, the natural
history of individuals with severe deficiency of AAT is less clear. Available
estimates of the yearly decline in FEV",
" _{",
" 1",
"}",
" among smokers range from as low as 42 to as high as 317 mL per year, compared
with 44 to 110 mL per year in nonsmokers or ex-smokers [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/3,30,55-59\">",
" 3,30,55-59",
" </a>",
" ]. The Registry of Patients with Severe Deficiency of Alpha-1 Antitrypsin, an
NHLBI-sponsored multicenter study of 1,129 patients, found an annual FEV",
" _{",
" 1",
"}",
" decline of 54 mL per year based upon high quality sequential pulmonary
function measurements [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/42,60\">",
" 42,60",
" </a>",
" ]. The rate of decline was higher (84 mL per year) among participants with
FEV",
" _{",
" 1",
"}",
" between 50 and 79 percent predicted who were not receiving augmentation
therapy. Similar findings were reported by the UK Antitrypsin Deficiency Assessment
and Programme for Treatment (ADAPT) [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/61\">",
" 61",
" </a>",
" ].",
" </p>",
" <p>",
" The prevalence of COPD among subjects with severe AAT deficiency has been
estimated to be 75 to 85 percent, with liver disease occurring in 12 to 16 percent.
One autopsy study indicated that cirrhosis occurred in 34 percent of decedents, of
whom 64 percent had cirrhosis suspected during life [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/62\">",
" 62",
" </a>",
" ].",
" </p>",
" <p>",
" The natural history of AAT deficiency has not been determined using
population-based studies. Mortality rates among AAT-deficient individuals that have
been reported using other types of studies [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/3,28,60,63\">",
" 3,28,60,63",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" A 37 percent mortality rate was observed in an 11-year follow-up study of
246 PI*Z homozygotes [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/28\">",
" 28",
" </a>",
" ]. Most deaths were ascribed to respiratory failure (59 percent), with a
minority of patients (13 percent) succumbing to complications of liver disease.",
" </li>",
" <li>",
" A second follow-up study (up to 7.2 years) noted a consistent 3 percent
annual mortality rate among the 1129 enrollees in the NHLBI-sponsored registry [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/63\">",
" 63",
" </a>",
" ]. Overall survival over the duration of this study was 82 percent. Most
deaths were caused by respiratory failure or liver disease (72 and 10 percent,
respectively). Mortality was closely associated with pulmonary function, and was
greatest for patients with an FEV",
" _{",
" 1",
"}",
" &lt;15 percent predicted (36 versus 3 percent for patients with FEV",
" _{",
" 1",
"}",
" &ge;50 percent predicted).",
" </li>",
" </ul>",
" </p>",
" <p>",
" Studies from the Danish Registry show that, in addition to FEV",
" _{",
" 1",
"}",
" , smoking status and method of ascertainment (ie, how the subject comes to the
attention of the registry) affect survival [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/64-66\">",
" 64-66",
" </a>",
" ].",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Survival among smokers and among patients with symptoms was lower than among
their nonsmoking asymptomatic counterparts [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/64,66\">",
" 64,66",
" </a>",
" ]. Furthermore, asymptomatic nonsmokers, who were usually identified as
relatives of symptomatic AAT-deficient individuals, had a survival rate equal to
that of the normal age-matched Danish population.",
" </li>",
" <li>",
" The FEV",
" _{",
" 1",
"}",
" was a major determinant of survival in AAT-deficient individuals, with the
mortality rising exponentially as FEV",
" _{",
" 1",
"}",
" falls below 35 percent of the predicted value (",
" <a class=\"graphic graphic_figure graphicRef81503 \" href=\"UTD.htm?
38/30/39405\">",
" figure 1",
" </a>",
" ). As an example, the two-year mortality rate among individuals with FEV",
" _{",
" 1",
"}",
" values of 15 percent predicted was almost 50 percent [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/65\">",
" 65",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Parameters other than FEV",
" _{",
" 1",
"}",
" have been used to predict mortality in patients with AAT-deficiency [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/67-71\">",
" 67-71",
" </a>",
" ]. As an example, decreased lung density as assessed by chest computed
tomographic (CT) scan was associated with increased mortality in a group of 256
AAT-deficient individuals followed for five years at a single center [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/68\">",
" 68",
" </a>",
" ].",
" </p>",
" <p>",
" In summary, survival estimates for subjects with severe deficiency of AAT vary
among series, presumably due to differences in study populations. Relatively normal
survival appears possible for nonsmoking asymptomatic individuals, although
survival estimates remain uncertain until long-term follow-up is done in a
population-based study [",
" <a class=\"abstract\" href=\"UTD.htm?6/8/6281/abstract/72,73\">",
" 72,73",
" </a>",
" ].",
" </p>",
" <p>",
" The favorable prognosis for this subgroup is consistent with expectations that
many individuals with severe deficiency are asymptomatic and therefore escape
medical attention. Patients with established airflow obstruction may derive long-
term benefit from AAT augmentation therapy, and, when airflow obstruction and
functional limitation is severe, should be considered for lung transplantation.
(See",
" <a class=\"medical medical_review\" href=\"UTD.htm?15/62/16361?
source=see_link\">",
" \"Treatment of alpha-1 antitrypsin deficiency\"",
" </a>",
" and",
" <a class=\"medical medical_review\" href=\"UTD.htm?26/20/26953?
source=see_link\">",
" \"Lung transplantation: General guidelines for recipient selection\"",
" </a>",
" .)",
" </p>",
" <p>",
" The American Thoracic Society (ATS) and European Respiratory Society (ERS)
statement on the diagnosis and management of AAT deficiency, as well as other ATS
guidelines, can be accessed through the ATS web site at",
" <a class=\"external\" href=\"file://www.thoracic.org/statements\">",
" www.thoracic.org/statements",
" </a>",
" .",
" </p>",
" <p class=\"headingAnchor\" id=\"H17\">",
" <span class=\"h1\">",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Alpha-1 antitrypsin (encoded by the gene PI, MIM +107400) is a member of the
serpin family of protease inhibitors. It protects the lower airways from damage
caused by the proteolytic enzyme, elastase. (See",
" <a class=\"local\" href=\"#H2\">",
" 'AAT phenotypes'",
" </a>",
" above.)",
" </li>",
" <li>",
" The normal alpha-1 antitrypsin allele is the M allele. Over 100 allelic
variants have been described, of which the most common severely deficient variant
is the Z allele. (See",
" <a class=\"local\" href=\"#H2\">",
" 'AAT phenotypes'",
" </a>",
" above.)",
" </li>",
" <li>",
" Severe deficiency of AAT is known to affect approximately 100,000 Americans.
However, AAT deficiency is severely under-recognized, with long intervals between
the first symptom and diagnosis. (See",
" <a class=\"local\" href=\"#H7\">",
" 'Epidemiology'",
" </a>",
" above.)",
" </li>",
" <li>",
" Clinical manifestations of severe deficiency of AAT typically involve the
lung (eg, early onset emphysema with a basilar predominant pattern on imaging),
liver (eg, cirrhosis), and, rarely, the skin (eg, panniculitis). (See",
" <a class=\"local\" href=\"#H10\">",
" 'Clinical manifestations'",
" </a>",
" above and",
" <a class=\"medical medical_review\" href=\"UTD.htm?17/45/18136?
source=see_link\">",
" \"Extrapulmonary manifestations of alpha-1 antitrypsin deficiency\"",
" </a>",
" .)",
" </li>",
" <li>",
" Patients with persistent airflow obstruction on spirometry should be tested
for AAT deficiency. Additional features that should lead to AAT deficiency testing
include emphysema in a young individual (eg, age &le;45 years), emphysema in a
nonsmoker or minimal smoker, emphysema characterized by predominant basilar changes
on the chest radiograph, a family history of emphysema",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" liver disease, current or prior panniculitis, and current or prior
unexplained chronic liver disease. (See",
" <a class=\"local\" href=\"#H13\">",
" 'Diagnosis'",
" </a>",
" above.)",
" </li>",
" <li>",
" The diagnosis of severe AAT deficiency is confirmed by demonstrating a serum
level below 11",
" <span class=\"nowrap\">",
" micromol/L",
" </span>",
" (~57",
" <span class=\"nowrap\">",
" mg/dL",
" </span>",
" by nephelometry) in combination with confirmation of a severe deficient
genotype, generally determined by isoelectric focusing or polymerase chain reaction
testing. (See",
" <a class=\"local\" href=\"#H13\">",
" 'Diagnosis'",
" </a>",
" above.)",
" </li>",
" <li>",
" The clinical manifestations of AAT deficiency during the first two to three
decades of life is that of liver disease, specifically chronic elevation of liver
enzymes or cirrhosis. (See",
" <a class=\"local\" href=\"#H14\">",
" 'Natural history'",
" </a>",
" above.)",
" </li>",
" <li>",
" Beyond the first two to three decades of life, patients with severe
deficiency of AAT have an accelerated rate of lung function decline, especially
with cigarette smoking and some occupational exposures. (See",
" <a class=\"local\" href=\"#H14\">",
" 'Natural history'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" <div id=\"topicAgreement\">",
" Use of UpToDate is subject to the",
" <a class=\"licenseLink\" href=\"./license\" id=\"sla_in_page\"
target=\"_blank\">",
" Subscription and License Agreement",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
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" Sveger T, Piitulainen E, Arborelius M Jr. Lung function in adolescents with
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" Wu MC, Eriksson S. Lung function, smoking and survival in severe alpha 1-
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" Buist AS, Burrows B, Eriksson S, et al. The natural history of air-flow
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" Dawkins PA, Dawkins CL, Wood AM, et al. Rate of progression of lung function
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" Seersholm N, Dirksen A, Kok-Jensen A. Airways obstruction and two year
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" Seersholm N, Kok-Jensen A. Clinical features and prognosis of life time non-
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" Shaker SB, Stavngaard T, Stolk J, et al. Alpha1-antitrypsin deficiency. 7:
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" Dowson LJ, Newall C, Guest PJ, et al. Exercise capacity predicts health
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" Dowson LJ, Guest PJ, Hill SL, et al. High-resolution computed tomography
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" </div>",
" <div class=\"lgnd\">",
" Monomorphous inflammatory papular eruption involving the trunk of a patient
treated with systemic corticosteroids.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 524px\">",
" <div class=\"ttl\">",
" Steroid acne",
" </div>",
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" Thoracic effects of radiation",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
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" <tr>",
" <td>",
" Pulmonary fibrosis",
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" <tr>",
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" Pulmonary vascular damage",
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" <td>",
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" <tr>",
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" <div class=\"footnotes\">",
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var title_f6_8_6284="Pretest probability of CHD";
var content_f6_8_6284=[" <div id=\"graphicsToolbar\">",
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" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
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" Age",
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" Men",
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" Women",
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" Men",
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" 22",
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" 94",
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" The probability values are expressed as the percent of patients with
significant coronary artery disease on angiography.",
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" </span>",
" </div>",
" <div class=\"reference\">",
" Combined data from Diamond GA, Forrester JS. N Engl J Med 1979; 300:1350; and
from Weiner DA, Ryan TJ, McCabe CH, et al. N Engl J Med 1979; 301:230.",
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AA7);\">",
" </div>",
" <div class=\"lgnd\">",
" The Numeric Pain Scale allows patients to rate the pain on a scale of 0 to 10,
with 10 as the worst possible pain.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_8_6285=[""].join("\n");
var outline_f6_8_6285=null;
var title_f6_8_6286="Using powder inhalers 1 PI";
var content_f6_8_6286=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=PI%2F51020%7EPI
%2F59737&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PI%2F51020%7EPI
%2F59737&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=2\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Technique for use of various dry powder inhalers - I",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Aerolizer",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove cover and hold the base of inhaler.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Twist mouthpiece in counter-clockwise direction.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove capsule from foil blister immediately before use and place capsule
in the base of the inhaler.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Hold the base of the inhaler and turn clockwise to close.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Simultaneously press both buttons once to pierce the capsule.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Exhale normally - do not exhale into the mouthpiece.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Tilt head back slightly, hold device horizontal with the buttons on the
left and right, place mouthpiece into the mouth, and close lips around
mouthpiece.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Breathe in rapidly and steadily, as deeply as possible; hold breath.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove device from mouth and exhale outside device.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Open chamber and examine capsule; if powder remains, repeat inhalation
process.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" After use, remove and discard capsule, and cover mouthpiece; store device
in cool, dry place.",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Diskhaler",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove mouthpiece cover and pull tray out from device.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Place disk on wheel with numbers facing up.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Rotate disk by sliding tray out and in.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Lift back of lid until fully upright so that needle pierces both sides of
blister.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Keep device level while inhaling dose with a rapid and steady flow.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Breathe in rapidly and steadily, as deeply as possible; hold breath.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove device from mouth and exhale outside device.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Brush off any powder remaining within device once every week; store device
in cool, dry place.",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Diskus",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Open the device and slide the lever until it clicks.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Keep device level while inhaling dose.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Breathe in rapidly and steadily, as deeply as possible; hold breath.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove device from mouth and exhale outside device; store device in cool,
dry place.",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\">",
" <div class=\"ttl\">",
" Technique for use of various dry powder inhalers - II",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\">",
" HandiHaler",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Capsules should be stored in sealed blisters and only removed immediately
before use.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Peel back the foil using the tab until one capsule is fully visible.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Open the dust cap by pulling it upwards, then open the mouthpiece.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Place the capsule in the center chamber (it does not matter which end of
the capsule is placed in the chamber).",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Close the mouthpiece firmly until you hear a click, leaving the dust cap
open.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Hold the HandiHaler with the mouthpiece upwards and press the piercing
button completely in once and release.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Breathe out completely. Do not breathe into the mouthpiece at any time.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Close your lips tightly around the mouthpiece.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Breathe in rapidly and steadily, as deeply as possible; hold breath.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" To ensure you get the full dose, repeat the inhalation from the HandiHaler
as described.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" After the dose, open the mouthpiece, tip out the used capsule, and
dispose. Do not handle used capsules.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Close the mouthpiece and dust cap for storage; store device in cool, dry
place.",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Turbuhaler",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Twist and remove cover.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Hold inhaler upright with mouthpiece facing up.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Turn grip right then left until it clicks.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Inhaler may be held upright or horizontal.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Breathe in rapidly and steadily, as deeply as possible; hold breath.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove device from mouth and exhale outside device.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Replace cover and twist to close; store device in cool, dry place.",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single\">",
" Twisthaler",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Hold the inhaler straight up with the pink portion (the base) on the
bottom.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove the cap while it is in the upright position to make sure you get
the right amount of medicine with each dose.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Hold the pink base and twist the cap in a counter-clockwise direction to
remove it.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" As you lift off the cap, the dose counter on the base will count down by
1. This action loads the medicine that you are now ready to inhale.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Make sure the indented arrow located on the white portion (directly above
the pink base) is pointing to the dose counter.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Breathe out normally - do not exhale into the device.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Place the mouthpiece into your mouth, with the mouthpiece facing towards
you, and close your lips tightly around it.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Inhale dose with a rapid and steady flow while holding the Twisthaler
horizontal.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Remove the mouthpiece from your mouth and hold your breath for 5 to 10
seconds (or as long as you comfortably can).",
" </td>",
" </tr>",
" <tr>",
" <td>",
" When you exhale, be sure that you are not exhaling into the device",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Immediately replace the cap and turn in a clockwise direction as you
gently press down until you hear a click.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Firmly close the Twisthaler to assure that your next dose is properly
loaded.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Be sure that the arrow is in line with the dose-counter window.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Store device in cool dry place.",
" </td>",
" </tr>",
" <tr>",
" <td>",
" The dose counter displays the number of doses remaining. When the unit
reads 01, this indicates the last remaining dose. When the counter reads 00, the
unit must then be discarded.",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" <div class=\"lgnd\">",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_8_6286=[""].join("\n");
var outline_f6_8_6286=null;
var title_f6_8_6287="X-linked recessive--pedigree";
var content_f6_8_6287=[" <div id=\"graphicsToolbar\">",
" <div id=\"graphicsCopy\">",
" &copy;2013 UpToDate",
" ^{",
" &reg;",
"}",
" </div>",
" <div id=\"graphicsLinks\">",
" <a href=\"?imageKey=PC
%2F55180&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\">",
" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
title=\"Print this page\"/>",
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PC
%2F55180&amp;source=image_view&amp;view=print&amp;elapsedTimeMs=1\" onclick=\"\"
title=\"Print this page\">",
" Print",
" </a>",
" <a class=\"etacLink\" href=\"#\">",
" <img alt=\"Email graphic(s)\" src=\"./../images/icn_email.myextg\"
title=\"Email graphic(s)\"/>",
" </a>",
" <a class=\"icontxt textLink etacLink\" href=\"#\" title=\"Email graphic(s)\">",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"graphic\">",
" <div class=\"figure\" style=\"width: 470px\">",
" <div class=\"ttl\">",
" Example of a pedigree showing X-linked recessive inheritance",
" </div>",
" <div class=\"cntnt\" style=\"width: 444px; height: 242px; background-image:
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" </div>",
" <div class=\"lgnd\">",
" X-linked recessive. Features of X-linked recessive inheritance seen here
include: male affection bias, lack of father-son transmission; 50 percent affected
status rate among sons of female carriers.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_8_6287=[""].join("\n");
var outline_f6_8_6287=null;