Getting a pop up <ref:url> out of context

mray · ‎Feb 22, 2016

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<!DOCTYPE StandardLetterBody PUBLIC "-//Aventis Pharmaceuticals//Standard Letter Body//EN" "file:C:\Users\NM28079\medinfo\XML_Standard_Letter_Body\StandardLetterBody.dtd">

<slb:DocumentProperties>

<DocumentTitle>Intracellular Concentration</DocumentTitle>

<TherapeuticArea>Respiratory</TherapeuticArea>

<GenericName>telithromycin</GenericName>

<TradeName>Ketek</TradeName>

<DocumentSubject>Pharmacokinetics-Pharmacodynamics</DocumentSubject>

<ChangeSummary>Final, added Barcia-Macay reference</ChangeSummary>

</slb:DocumentProperties>

<slb:DocumentContent>

<sect1>

<title>As stated in the KETEK package insert:<ref:reference confidentiality="Public" object_id="09012bda8001f259" xmlns:ref="ref"><ref:packageinsert><ref:tradename>Ketek</ref:tradename><ref:companylocation>Bridgewater, NJ</ref:companylocation><ref:companyname>sanofi-aventis U.S.</ref:companyname><ref:publicationdate>2010</ref:publicationdate></ref:packageinsert></ref:reference></title>

<para><emphasis role="bold">CLINICAL PHARMACOLOGY</emphasis></para>

<para><emphasis role="bold"><emphasis role="underline">Pharmacokinetics</emphasis></emphasis></para>

<para><emphasis role="bold">Distribution:</emphasis></para>

<para>Telithromycin concentrations in ...alveolar macrophages after

800 mg once daily dosing for 5 days in patients are displayedin Table

2.</para>

<?PubTbl tgroup dispwid="6.64in"?>

<tbody>

<row>

<entry nameend="col5" namest="col1" rowsep="0"><emphasis role="bold">Table 2</emphasis></entry>

</row>

<row>

<entry colsep="1" nameend="col5" namest="col3">Mean concentration

(µg/mL)</entry>

</row>

<row>

<entry><para><emphasis role="bold">Hours</emphasis><?Pub _newline

?><emphasis role="bold">post-</emphasis><?Pub _newline?><emphasis role="bold">dose</emphasis></para></entry>

<entry valign="bottom"><para><emphasis role="bold">Tissue or</emphasis><?Pub _newline?><emphasis role="bold">fluid</emphasis></para></entry>

<entry valign="bottom"><para><emphasis role="bold">Plasma</emphasis></para></entry>

<entry><para><emphasis role="bold">Tissue/</emphasis><?Pub _newline

?><emphasis role="bold">Plasma</emphasis><?Pub _newline?><emphasis role="bold">Ratio</emphasis></para></entry>

</row>

<row>

<entry>Alveolar macrophages</entry>

<entry align="center"><para>1.07<?Pub _newline?>0.605<?Pub _newline

?>0.073</para></entry>

</row>

</tbody>

</tgroup>

</informaltable>

<para>Telithromycin concentration in white blood cells exceeds the

concentration in plasma and is eliminated more slowly from white blood

cells than from plasma. Mean white blood cell concentrations of telithromycin

peaked at 72.1 µg/mL at 6 hours, and remained at 14.1 µg/mL

24 hours after 5 days of repeated dosing of 600 mg once daily. After

10 days, repeated dosing of 600 mg once daily, white blood cell concentrations

remained at 8.9 µg/mL 48 hours after the last dose.</para>

<para><emphasis role="underline"><emphasis role="bold">Microbiology</emphasis></emphasis></para>

<para>...Telithromycin concentrates in phagocytes where it exhibits

activity against intracellular respiratory pathogens...</para>

</blockquote>

<para>Telithromycin, a ketolide<ref:reference confidentiality="Public" object_id="09012bda8001b69f" xmlns:ref="ref"><ref:journalarticle><ref:author>Blaney SM</ref:author><ref:author>Seibel NL</ref:author><ref:author>O'Brien M</ref:author><ref:author>Reaman GH</ref:author><ref:author>Berg SL</ref:author><ref:author>Adamson PC</ref:author><ref:author>Poplack DG</ref:author><ref:author>Krailo MD</ref:author><ref:author>Mosher R</ref:author><ref:author>Balis FM</ref:author><ref:journaltitle>Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative Pediatric Branch, National Cancer Institute and Children's Cancer Group trial</ref:journaltitle><ref:serialtitle>J Clin Oncol</ref:serialtitle><ref:publicationdate>1997</ref:publicationdate><ref:volume>15</ref:volume><ref:issuenumber>4</ref:issuenumber><ref:firstpage>1538</ref:firstpage><ref:lastpage>1543</ref:lastpage></ref:journalarticle></ref:reference> having a keto-group rather than

a sugar (L-cladinose) at position 3 of the lactone ring, is a derivative

of the macrolide antibiotics. Macrolide antibiotics concentrate within

host cells, a characteristic responsible for activity against intracellular

pathogens and modulation of cell metabolism and function.<ref:reference confidentiality="Public" object_id="09012bda8001f8af" xmlns:ref="ref"><ref:journalarticle><ref:author>Labro MT</ref:author><ref:author>Abdelghaffar H</ref:author><ref:journaltitle>Immunomodulation by macrolide antibiotics</ref:journaltitle><ref:serialtitle>J Chemother</ref:serialtitle><ref:publicationdate>2001</ref:publicationdate><ref:volume>13</ref:volume><ref:issuenumber>1</ref:issuenumber><ref:firstpage>3</ref:firstpage><ref:lastpage>8</ref:lastpage></ref:journalarticle></ref:reference> Telithromycin

has been documented to accumulate within various cells.<ref:reference confidentiality="Confidential" object_id="09012bda8001f3fa" xmlns:ref="ref"><ref:studyreport><ref:studyreportnumber>NDA 21-144 Original</ref:studyreportnumber></ref:studyreport></ref:reference> <hiddentext xmlns:ref="ref">(NDA Section 7.B.1.2.5.4, 7:v001:p172–176)</hiddentext> At an extracellular concentration of 2.5 µg/mL, telithromycin

gradually accumulates in polymorphonuclear neutrophils (PMNs) with

an intracellular/extracellular concentration ratio (C/E) ranging from

27.0 ± 8.1 (at 5 minutes) to 348 ± 27.1 (at 160 minutes).

At an extracellular concentration of 2 µg/mL, telithromycin

uptake into macrophages is also rapid with a C/E ratio of 65 (at 60

minutes). </para><?Pub Caret 25?>

</sect1>

<sect1>

<title>Intracellular Kinetics of Telithromycin</title>

<para>The ability of telithromycin to enter PMNs, peripheral blood

mononuclear cells and cells of hematopoietic and nonhematopoietic

origin was investigated <emphasis role="italic">in vitro</emphasis>.<ref:reference confidentiality="Public" object_id="09012bda8001f8b1" xmlns:ref="ref"><ref:journalarticle><ref:author>Miossec-Bartoli C</ref:author><ref:author>Pilatre L</ref:author><ref:author>Peyron P</ref:author><ref:author>N'Diaye EN</ref:author><ref:author>Collart-Dutilleul V</ref:author><ref:author>Maridonneau-Parini I</ref:author><ref:author>Diu-Hercend A</ref:author><ref:journaltitle>The new ketolide HMR3647 accumulates in the azurophil granules of human polymorphonuclear cells.</ref:journaltitle><ref:serialtitle>Antimicrob Agents Chemother</ref:serialtitle><ref:publicationdate>1999</ref:publicationdate><ref:volume>43</ref:volume><ref:issuenumber>10</ref:issuenumber><ref:firstpage>2457</ref:firstpage><ref:lastpage>2462</ref:lastpage></ref:journalarticle></ref:reference> Telithromycin was slowly taken up into PMNs achieving a C/E concentration

ratio around 300 after 2 hours. It concentrated and remained within

the cells, with 80% of the drug remaining cell associated after 2

hours. Subcellular fractionation of the PMNs showed that the majority

of telithromycin resides within the azurophil granules. Incorporation

of telithromycin into other cell types (peripheral blood mononuclear

cells, T-lymphocytic cells, monocytic cells, erythroid progenitor

cell types, promyelocytic cell line and colon carcinoma cell line)

was poor with quick release.</para>

<para>In order for an antimicrobial agent to be effectively transported

to a location of infection, it must not interfere with the ability

of the neutrophil to sense chemoattractants and to move normally.

A study was performed to evaluate the effect of telithromycin on

these properties in an <emphasis role="italic">in vitro</emphasis> model utilizing <emphasis role="italic">Streptococcus pyogenes</emphasis>, <emphasis role="italic">Staphylococcus aureus</emphasis>, <emphasis role="italic">Escherichia coli</emphasis>, and <emphasis role="italic">Micrococcus luteus</emphasis>.<ref:reference confidentiality="Public" object_id="09012bda8001f8b3" xmlns:ref="ref"><ref:journalarticle><ref:author>Mandell GL</ref:author><ref:author>Coleman E</ref:author><ref:journaltitle>Uptake, transport, and delivery of antimicrobial agents by human polymorphonuclear neutrophils.</ref:journaltitle><ref:serialtitle>Antimicrob Agents Chemother</ref:serialtitle><ref:publicationdate>2001</ref:publicationdate><ref:volume>45</ref:volume><ref:issuenumber>6</ref:issuenumber><ref:firstpage>1794</ref:firstpage><ref:lastpage>1798</ref:lastpage></ref:journalarticle></ref:reference> Among the agents tested (penicillin G, azithromycin, ciprofloxacin,

levofloxacin, and moxifloxacin), telithromycin was documented to be

highly concentrated and slowly released from PMNs. Telithromycin

was transported by PMNs towards a chemoattractant, resulting in zones

of bacterial inhibition that were greater than those reported for

the other agents tested. </para>

<para>The intracellular kinetics of telithromycin, its effects on

pro-inflammatory cytokines, and its effect on PMN bactericidal activity

was examined in a series of<emphasis role="italic"> in vitro</emphasis> studies. Telithromycin was shown to concentrate in PMNs displaying

a C/E concentration ratio of 31 ± 4.2 at 5 minutes up to 348

± 27.1 at 180 minutes.<ref:reference confidentiality="Public" object_id="09012bda8001f81c" xmlns:ref="ref"><ref:journalarticle><ref:author>Vazifeh D</ref:author><ref:author>Preira A</ref:author><ref:author>Bryskier A</ref:author><ref:author>Labro MT</ref:author><ref:journaltitle>Interactions between HMR 3647, a new ketolide, and human polymorphonuclear neutrophils</ref:journaltitle><ref:serialtitle>Antimicrob Agents Chemother</ref:serialtitle><ref:publicationdate>1998</ref:publicationdate><ref:volume>42</ref:volume><ref:issuenumber>8</ref:issuenumber><ref:firstpage>1944</ref:firstpage><ref:lastpage>1951</ref:lastpage></ref:journalarticle></ref:reference> It was noted

that approximately 60% of telithromycin was concentrated in the granular

compartment of PMNs and the intracellular uptake displayed Michaelis-Menten

saturation kinetics. Uptake was dependent on environmental temperatures

and extracellular calcium was necessary for optimal uptake. Telithromycin

weakly triggered granule exocytosis from PMNs and inhibited superoxide

anion production (oxidative burst) in a time and concentration-dependent

manner. </para>

<para>The effects of various proinflammatory cytokines (interleukin

1 [IL-1], IL-6, IL-8, gamma interferon, tumor necrosis factor alpha

(TNF-a) and granulocyte-macrophage colony stimulating factor (GM-CSF)

on cellular uptake of telithromycin and the interaction of telithromycin

with polymorphonuclear neutrophils (PMN) has been investigated.<ref:reference confidentiality="Public" object_id="09012bda8001bcf7" xmlns:ref="ref"><ref:journalarticle><ref:author>Vazifeh D</ref:author><ref:author>Bryskier A</ref:author><ref:author>Labro MT</ref:author><ref:journaltitle>Effect of proinflammatory cytokines on the interplay between roxithromycin, HMR 3647, or HMR 3004 and human polymorphonuclear neutrophils</ref:journaltitle><ref:serialtitle>Antimicrob Agents Chemother</ref:serialtitle><ref:publicationdate>2000</ref:publicationdate><ref:volume>44</ref:volume><ref:issuenumber>3</ref:issuenumber><ref:firstpage>511</ref:firstpage><ref:lastpage>521</ref:lastpage></ref:journalarticle></ref:reference> In this study, TNF-a and GM-CSF were the only cytokines to exert

an effect on telithromycin, lessening the inhibitory effects of telithromycin

on PMN oxidant production. Inhibitory concentrations suggest that

telithromycin acts downstream of the priming effect of TNF-a and GM-CSF.

TNF-a and GM-CSF also modestly decreased the PMN uptake of telithromycin

by approximately 20%.</para>

<para>In the final study, the effects of telithromycin on bactericidal

activity of PMNs was studied utilizing four strains of Staphylococcus

aureus with different profiles of susceptibility to macrolides and

ketolides.<ref:reference confidentiality="Public" object_id="09012bda8001f8b5" xmlns:ref="ref"><ref:journalarticle><ref:author>Vazifeh D</ref:author><ref:author>Abdelghaffar H</ref:author><ref:author>Labro MT</ref:author><ref:journaltitle>Effect of telithromycin (HMR 3647) on polymorphonuclear neutrophil killing of Staphylococcus aureus in comparison with roxithromycin.</ref:journaltitle><ref:serialtitle>Antimicrob Agents Chemother</ref:serialtitle><ref:publicationdate>2002</ref:publicationdate><ref:volume>46</ref:volume><ref:issuenumber>5</ref:issuenumber><ref:firstpage>1364</ref:firstpage><ref:lastpage>1374</ref:lastpage><ref:url>www.ggggle.com</ref:url></ref:journalarticle></ref:reference> The effects of intracellular bacteria on cellular uptake of telithromycin

was also evaluated. High concentrations of telithromycin, which abolished

the oxidative metabolism of the PMNs, did not impair bactericidal

function. In a global assay, the bactericidal activity of telithromycin

was not impaired in the presence of PMNs. The authors concluded that

the antibacterial activity of telithromycin against <emphasis role="italic" xmlns:ref="ref">S. aureus</emphasis> in this setting

was a direct effect of the drug, and not due to a synergistic interaction

with the bactericidal system of the PMNs. </para>

<para>The activity of telithromycin against intracellular <emphasis role="italic">Legionella pneumophilia</emphasis> was investigated

in an <emphasis role="italic">in vitro</emphasis> study using human

monocytes.<ref:reference confidentiality="Public" object_id="09012bda8001f8b6" xmlns:ref="ref"><ref:journalarticle><ref:author>Baltch AL</ref:author><ref:author>Smith RP</ref:author><ref:author>Ritz WJ</ref:author><ref:author>Franke MA</ref:author><ref:author>Michelsen PB</ref:author><ref:journaltitle>Antibacterial effect of telithromycin (HMR 3647) and comparative antibiotics against intracellular Legionella pneumophila.</ref:journaltitle><ref:serialtitle>J Antimicrob Chemother</ref:serialtitle><ref:publicationdate>2000</ref:publicationdate><ref:volume>46</ref:volume><ref:issuenumber>1</ref:issuenumber><ref:firstpage>51</ref:firstpage><ref:lastpage>55</ref:lastpage></ref:journalarticle></ref:reference> Telithromycin (10X MIC for 4 days) produced a significant antimicrobial

effect on monocytes exposed to <emphasis role="italic" xmlns:ref="ref">L. pneumophlia</emphasis>. There were no significant differences

observed with regards to the growth of intracellular <emphasis role="italic" xmlns:ref="ref">L. pneumophilia</emphasis> on days 2-4

when telithromycin was removed following 1 day of exposure. The authors

noted that removal of telithromycin did not affect the continued antimicrobial

activity of the monocytes. </para>

<para>Telithromycin's intracellular activity against <emphasis role="italic">S. aureus </emphasis> ATCC 25493 (MIC 2 mg/L) was evaluated

in human THP-1 macrophages infection model.<ref:reference confidentiality="Public" object_id="09012bda80020c90" xmlns:ref="ref"><ref:abstract><ref:author>Barcia-Macay M</ref:author><ref:author>Seral C</ref:author><ref:author>Mingeot-Leclercq MP</ref:author><ref:author>Tulkens PM</ref:author><ref:abstracttitle>Comparative activity of 12 antibiotics (ABs) used at clinically-meaningful extracellular concentration against S. aureus in broth and in human THP-1 macrophages</ref:abstracttitle><ref:conference>43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, September 14-17, 2003</ref:conference><ref:abstractnumber>A-1174</ref:abstractnumber></ref:abstract></ref:reference> At a concentration of 2 mg/L, telithromycin's

extracellular and intracellular activities were -1.84±0.02

log change in cfu in 24 hours in broth and –1.14±0.04

log change in cfu in 24 hours in human THP-1 macrophages, respectively.</para>

<para>A study evaluated the effect of P-glycoprotein inhibitors (cyclosporin

A, verapamil, GF120918) on the accumulation and efflux of telithromycin

in J774 murine macrophages.<ref:reference confidentiality="Public" object_id="09012bda8001fd82" xmlns:ref="ref"><ref:journalarticle><ref:author>Seral C</ref:author><ref:author>Michot J-M</ref:author><ref:author>Chanteux H</ref:author><ref:author>Mingeot-Leclercq M-P</ref:author><ref:author>Tulkens PM</ref:author><ref:author>Van Bambeke F</ref:author><ref:journaltitle>Influence of p-glycoprotein inhibitors on accumulation of macrolides in J774 murine macrophages</ref:journaltitle><ref:serialtitle>Antimicrob Agents Chemother</ref:serialtitle><ref:publicationdate>2003</ref:publicationdate><ref:volume>47</ref:volume><ref:issuenumber>3</ref:issuenumber><ref:firstpage>1047</ref:firstpage><ref:lastpage>1051</ref:lastpage></ref:journalarticle></ref:reference> In the presence of the inhibitors, there was a 2– to 3.5–fold

increase in the rate of telithromycin accumulation in the macrophages;

however, the efflux of telithromycin from the macrophages was slowed

marginally. Cyclosporin and GF120918 increased the accumulation of

telithromycin in the macrophages by 3– to 4–fold following

3 hours of cell incubation with extracellular telithromycin (5 mg/L).

The effect of verapamil on telithromycin was lower than the effect

of the other inhibitors (P < 0.05). The authors concluded that

the data strongly suggests that modulation of P-glycoprotein is responsible

for the observed effects on the accumulation of telithromycin. They

stated that the conclusions for the study were limited to J774 murine

macrophages and could not be applied to other phagocytic cells. The

effects of the efflux proteins on the intracellular activity of telithromycin

may need to be studied systematically.</para>

</sect1>

<sect1>

<title>Penetration of Telithromycin into WBCs and Alveolar Macrophages</title>

<para>The intracellular accumulation and concentration of telithromycin

in white blood cells (WBC) was studied in blood samples obtained from

healthy male volunteers.<ref:reference confidentiality="Public" object_id="09012bda8001f808" xmlns:ref="ref"><ref:poster><ref:author>Gia HP</ref:author><ref:author>Roeder V</ref:author><ref:author>Namour F</ref:author><ref:author>Sultan E</ref:author><ref:author>Lenfant B</ref:author><ref:postertitle>Telithromycin (HMR 3647) achieves high and sustained concentrations in white blood cells in man</ref:postertitle><ref:conference>5th International Conference on Macrolides, Azalides, Streptogramins, Ketolides, and Oxazolidinones, Seville, Spain, January 26-28, 2000</ref:conference><ref:posternumber>09.27</ref:posternumber></ref:poster></ref:reference> Following administration of either a

single oral dose of telithromycin 600 mg or the same dose administered

once daily for 10 days, WBC and plasma concentrations of telithromycin

as well as the WBC concentration/plasma concentration ratio and area

under the concentration-time curve (AUC) in WBCs and plasma were assessed.

It was reported that telithromycin rapidly concentrates in WBCs following

a single oral dose, reaching 44-fold greater levels than in plasma

1 hour after dosing and increasing to 705 at 24 hours post-dose.

The WBC/plasma concentration ratio ranged from 87 at 2 hours post-dose

on Day 5 to 2201 at 48 hours post-dose on Day 10. The ratio of the

AUC (0-24 hours) for WBC to the AUC(0-24 hours) for plasma on Day

10 of the multiple dose study was 242. The telithromycin concentration

in WBCs exceeded the minimum inhibitory concentration of respiratory

pathogens up to 48 hours following multiple dosing. The authors concluded

that the data suggest a role for telithromycin against intracellular

pathogens.</para>

<para>The penetration of telithromycin into bronchopulmonary tissues

(alveolar macrophages (AM) and epithelial lining fluid (ELF)) was

evaluated in healthy male volunteers.<ref:reference confidentiality="Public" object_id="09012bda8001f7cc" xmlns:ref="ref"><ref:journalarticle><ref:author>Muller-Serieys C</ref:author><ref:author>Soler P</ref:author><ref:author>Cantalloube C</ref:author><ref:author>Lemaitre F</ref:author><ref:author>Gia HP</ref:author><ref:author>Brunner F</ref:author><ref:author>Andremont A</ref:author><ref:journaltitle>Bronchpulmonary disposition of the ketolide telithromycin (HMR 3647)</ref:journaltitle><ref:serialtitle>Antimicrob Agents Chemother</ref:serialtitle><ref:publicationdate>2001</ref:publicationdate><ref:volume>45</ref:volume><ref:issuenumber>11</ref:issuenumber><ref:firstpage>3104</ref:firstpage><ref:lastpage>3108</ref:lastpage></ref:journalarticle></ref:reference> Following a 5–day course of oral telithromycin 800 mg once

daily, patients underwent fiberoptic bronchoscopy and bronchoalveolar

lavage at 2, 8, 24, or 48 hours. Concentrations of telithromycin

in both AM and ELF were significantly greater than those in plasma

at each time point (P<0.05). Telithromycin was retained in AM

24 hours after dosing and was quantifiable 48 hours after dosing.

The authors concluded that while the data were obtained from noninfected

subjects, it was unlikely that infection would reduce the concentration

of telithromycin in AM and ELF.</para>

<para>In a study of 20 patients undergoing elective bronchoscopy,

the mean concentration of telithromycin in alveolar macrophages (AM),

epithelial lining fluid (ELF), and bronchial mucosal (BM) were measured

2, 12, and 24 hours after the last dose of a 5–day course of

oral telithromycin 800 mg once daily.<ref:reference confidentiality="Public" object_id="09012bda8001b980" xmlns:ref="ref"><ref:journalarticle><ref:author>Khair OA</ref:author><ref:author>Andrews JM</ref:author><ref:author>Honeybourne D</ref:author><ref:author>Jevons G</ref:author><ref:author>Vacheron F</ref:author><ref:author>Wise R</ref:author><ref:journaltitle>Lung concentrations of telithromycin after oral dosing</ref:journaltitle><ref:serialtitle>J Antimicrob Chemother</ref:serialtitle><ref:publicationdate>2001</ref:publicationdate><ref:volume>47</ref:volume><ref:issuenumber>6</ref:issuenumber><ref:firstpage>837</ref:firstpage><ref:lastpage>840</ref:lastpage></ref:journalarticle></ref:reference> Telithromycin concentrations

in AM, ELF, and BM were higher (161.57 mg/L, 0.97 mg/L, and 0.78 mg/L,

respectively) than the plasma concentration (0.08 mg/L) at 24 hours

post-dose. At 24 hours post dose, the concentration of telithromycin

in BM and ELF was greater than the MIC90 for the common respiratory

pathogens, <emphasis role="italic" xmlns:ref="ref">Streptococcus pneumoniae</emphasis> (0.12 mg/L) and <emphasis role="italic" xmlns:ref="ref">Moraxella

catarrhalis</emphasis> (0.03 mg/L) as well as the atypical pathogen <emphasis role="italic" xmlns:ref="ref">Mycoplasma pneumoniae</emphasis> (0.001

mg/L). The telithromycin concentration in BM and ELF exceeded the

MIC90 for <emphasis role="italic" xmlns:ref="ref">Haemophilus influenzae</emphasis> (2 mg/L) for 12 hours.</para>

</sect1>

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</StandardLetterBody><?Pub *0000024884?>

TimPhelps · ‎Feb 22, 2016

Is ref:url defined in the DTD for the ref namespace?

I see it used in your document as

<ref:url>www.ggggle.com</ref:url>

The xml syntax look correct.

What is the definition of the content of ref:url? CDATA?

mray · ‎Feb 22, 2016

Thanks for your response.

ref:url is mentioned as #PCDATA

Following is the DTD:

<?xml version='1.0' encoding='UTF-8' ?>

<!ENTITY % hidden SYSTEM "hidden.dtd">
%hidden;

<!ATTLIST ref:reference    xmlns:ref CDATA #FIXED "ref"
      object_id       CDATA #IMPLIED
                           confidentiality CDATA #IMPLIED
                           language        CDATA #IMPLIED
                           therapeuticarea CDATA #IMPLIED
                           genericname     CDATA #IMPLIED
>
<!ELEMENT ref:journalarticle (ref:author* , ref:journaltitle? , ref:serialtitle? , ref:publicationdate? , ref:url? , ref:volume? , ref:issuenumber? , ref:firstpage? , ref:lastpage?)>

<!ELEMENT ref:book (ref:author* , ref:booktitle? , ref:editor* , ref:volumenumber? , ref:volumetitle? , ref:edition? , ref:publisherlocation? , ref:publisher? , ref:publicationdate? , ref:url? )>

<!ELEMENT ref:bookchapter (ref:author* , ref:chaptertitle? , ref:editor* , ref:booktitle? , ref:volumetitle? , ref:edition? , ref:publisherlocation? , ref:publisher? , ref:publicationdate? , ref:url? , ref:firstpage? , ref:lastpage?)>

<!ELEMENT ref:abstract (ref:author* , ref:abstracttitle? , ((ref:serialtitle, ref:publicationdate?) | ref:conference)? , ref:url? , ref:volume? , ref:issuenumber? , ref:firstpage? , ref:lastpage? , ref:abstractnumber?)>

<!ELEMENT ref:poster (ref:author* , ref:postertitle? , ((ref:serialtitle, ref:publicationdate?) | ref:conference)? , ref:url? , ref:volume? , ref:issuenumber? , ref:firstpage? , ref:lastpage? , ref:posternumber?)>

<!ELEMENT ref:studyreport (ref:studyreportnumber?, ref:url? )>

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<!ELEMENT ref:monographpamphlet (ref:title?, ref:companyname?, ref:publicationdate? , ref:url? , ref:advertisingcode?)>

<!ELEMENT ref:website (ref:author* , ref:title? , ref:url? , ref:accessdate?)>

<!ELEMENT ref:miscellaneous (ref:referencecontent?, ref:url? )>

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<!ELEMENT ref:msds (ref:tradename? , ref:msdsdate?, ref:msdsdate?, ref:url? )>

<!ELEMENT ref:cdromslidekit (ref:title? , ref:companyname? , ref:publicationdate?, ref:url? )>

<!ELEMENT ref:packageinsert (ref:tradename?, ref:companylocation?, ref:companyname? , ref:publicationdate?, ref:url? )>

<!ELEMENT ref:author (#PCDATA)>

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<!ELEMENT ref:companylocation (#PCDATA)>

<!ELEMENT ref:hiddenreferences (hid:reference+)>

TimPhelps · ‎Feb 23, 2016

Your DTD does not allow a <ref:url> to follow a <ref:firstpage> or <ref:lastpage> as seen in

</ref:issuenumber><ref:firstpage>1364</ref:firstpage><ref:lastpage>1374</ref:lastpage><ref:url>www.ggggle.com</ref:url></ref:journalarticle></ref:reference>

rdiaz · ‎May 27, 2016

Mandakini,

Were you able to resolve this with Tim's comments?