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  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">AED</journal-id>
      <journal-id journal-id-type="doi">10.1159/issn.2235-8595</journal-id>
      <journal-id journal-id-type="book_series">Aesthetic Dermatology</journal-id>
      <journal-title-group>
        <journal-title>Cosmetic Photodynamic Therapy</journal-title>
      </journal-title-group>
      <issn pub-type="ppub">22</issn>
      <issn pub-type="epub">2235-8595</issn>
      <isbn>978-3-318-02556-9</isbn>
      <isbn content-type="e-isbn">978-3-318-02557-6</isbn>
      <publisher>
        <publisher-name>S. Karger AG</publisher-name>
        <publisher-loc>Basel, Switzerland<email xlink:href="mailto:karger@karger.com" /><uri xlink:href="http://www.karger.com" /></publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">439327</article-id>
      <article-id pub-id-type="doi">10.1159/000439327</article-id>
      <article-id pub-id-type="other">Gold MH (ed): Cosmetic Photodynamic Therapy. Aesthet Dermatol. Basel, Karger, 2016, vol 3, pp 1-7</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Chapter</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>A Historical Look at Photodynamic Therapy</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Gold</surname>
            <given-names>Michael H.</given-names>
          </name>
        </contrib>
        <contrib contrib-type="editor">
          <name>
            <surname>Gold</surname>
            <given-names>M.H.</given-names>
          </name>
          <xref ref-type="contrib" />
        </contrib>
      </contrib-group>
      <aff>Gold Skin Care Center, Tennessee Clinical Research Center, and Division of Dermatology, Department of Medicine, Vanderbilt University School of Nursing, and School of Medicine, Meharry Medical College, Nashville, Tenn., USA</aff>
      <author-notes>
        <corresp id="cor1">*Michael H. Gold, MD, Gold Skin Care Center, Tennessee Clinical Research Center, 2000 Richard Jones Road, Suite 220, Nashville, TN 37215 (USA), E-Mail drgold@goldskincare.com</corresp>
      </author-notes>
      <pub-date pub-type="subscription-year">
        <year>2015</year>
      </pub-date>
      <pub-date pub-type="ppub">
        <month>02</month>
        <year>2016</year>
      </pub-date>
      <pub-date pub-type="epub">
        <day>01</day>
        <month>02</month>
        <year>2016</year>
      </pub-date>
      <volume>3</volume>
      <fpage>1</fpage>
      <lpage>7</lpage>
      <permissions>
        <copyright-statement>© 2016 S. Karger AG, Basel</copyright-statement>
        <copyright-year>2016</copyright-year>
        <license license-type="all-rights-reserved" xlink:href="https://www.karger.com/Services/SiteLicenses">
          <license-p>Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. 
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. 
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
</license-p>
        </license>
      </permissions>
      <self-uri xlink:href="https://www.karger.com/Article/Pdf/439327" content-type="application/pdf" />
      <self-uri xlink:href="https://www.karger.com/Article/FullText/439327" content-type="text/html" />
      <abstract>
        <p>Many dermatologists who utilize photodynamic therapy (PDT) in their everyday clinical practices assume that PDT is a fairly new therapeutic modality. In fact, and surprising to many, PDT has been available in medicine since the beginning of the 20th century. In this review, we will trace some of the major roots of PDT and how it ended up in the capable hands of dermatologists, many of whom utilize the treatment on a daily basis for the well-being of their patients with a variety of skin concerns.</p>
      </abstract>
      <counts>
        <fig-count count="2" />
        <table-count count="1" />
        <ref-count count="10" />
        <page-count count="7" />
      </counts>
    </article-meta>
    <notes notes-type="article-type-status">
      <p>verified</p>
    </notes>
  </front>
  <body>
    <sec>
      <title />
      <p>The beginnings of photodynamic therapy (PDT) history can be traced to the year 1900, when Raab [<xref ref-type="bibr" rid="ref1">1</xref>] first described an experiment that was conducted with cells from <italic>Paramecium caudatum</italic>. He noted that the paramecium cells were not affected in any way when they were exposed to either acridine orange or a light source alone. But he noted that if the paramecium cells were exposed to the acridine orange and the light source at the same time, the same cells died within 2 h of this exposure. This was the first report of how PDT would come to be - the use of a photosensitizer, in this case acridine orange, and a light source to cause an effect on a cell, in this case, cell death.</p>
      <p>Several years later, in 1904, von Tappeiner and Jodblauer [<xref ref-type="bibr" rid="ref2">2</xref>] termed the expression <italic>photodynamic effect</italic> as they described their experiments in which an oxygen-consuming reaction in protozoa was noted after aniline dyes were applied to the protozoa with fluorescence. The following year, in 1905, Jesionek and von Tappeiner [<xref ref-type="bibr" rid="ref3">3</xref>] reported on their experiences with a topical 5% eosin as a photosensitizer in their experiments on PDT. Topical 5% eosin was used successfully as a photosensitizer with an artificial light source to successfully treat a variety of dermatologic skin conditions common in the day, including nonmelanoma skin cancers, lupus vulgaris, and condylomata lata. The researchers postulated that the topical eosin that was being applied to the lesions could be incorporated into the cells, as was noted with acridine orange earlier, and, once in the appropriate cells, could produce a cytotoxic reaction when the lesions were exposed to an appropriate light source in the presence of oxygen. These early, pioneering experiments and studies were in fact the first reports of PDT in human subjects and became the prototype for all the future interest and scientific awareness in the field of PDT, and we are fortunate to note that dermatologic skin concerns were where the origins of the study of PDT began, which now reaches far and wide. The concept described in 1905 on which PDT works still holds steadfast today. An appropriate photosensitizer applied to the skin can be absorbed into appropriate and specific cells within the skin, and in the presence of oxygen and an appropriate light source can produce a phototoxic reaction within those skin cells, leading to a photodynamic effect and cell death in that particular cell.</p>
      <p>Soon after these reports on what we now know was PDT, other researchers began looking at PDT and, specifically, the photosensitizers that could be used to potentially make the process even better than what had earlier been described. The PDT field turned its attention to the use of porphyrins as photosensitizers. In 1911, Hausman et al. [<xref ref-type="bibr" rid="ref4">4</xref>] reported on the use of hematoporphyrin as a possible photosensitizer. The group was able to show successfully that hematoporphyrin could be used as a photosensitizer when exposed to light and oxygen in both guinea pigs and in mice. Meyer-Betz [<xref ref-type="bibr" rid="ref5">5</xref>], in 1913, decided that it was necessary to study the hematoporphyrin in humans and since this had not been done before, he self-injected the photosensitizer into his own skin. What he noted was that when the injected areas were exposed to a light source, the areas injected became swollen and painful. And he observed that the phototoxic reaction that he was experiencing was not a self-limited one, in that the phototoxic reaction that he had been experiencing continued for 2 full months. Although hematoporphyrin is successful as a photosensitizer, the fact that it was not self-limiting made it difficult for clinicians of the day to use it on actual patients, and interest waned on how best to use PDT in everyday medicine and dermatology.</p>
      <p>It was not until 1942 that interest once again with hematoporphyrin resurfaced in dermatology. Auler and Banzer [<xref ref-type="bibr" rid="ref6">6</xref>] reported that hematoporphyrin was concentrating in certain dermatologic skin tumors and not in the surrounding structures around the tumors. They also noted that when the tumors were fluoresced with light, the tumors became necrotic over time, leaving the remaining skin normal. This again explained the uniqueness of PDT for use in medicine and for selective destruction of a target tissue in dermatology. Several years later, Figge et al. [<xref ref-type="bibr" rid="ref7">7</xref>] reported their findings with the use of hematoporphyrin as a photosensitizer. They noted that hematoporphyrin could be selectively absorbed into other cells within the body, specifically embryonic cells, traumatized skin cells, and in certain neoplastic cells.</p>
      <p>From these humble beginnings, the groundwork for the use of PDT in medicine, and specifically in dermatology, had been laid out for us to continue to study, evaluate, and work with photosensitizers that were easily available, easily applied to the skin, and would carry out the photodynamic reaction with minimal adverse events. That became the next challenge for the PDT researchers of the day. The principle of PDT, i.e. the use of a photosensitizer, which now became hematoporphyrin for dermatologic research, which was selectively absorbed into cancerous skin cells, could be activated by an appropriate light source, and, in the presence of oxygen, cause selective destruction of the cancerous cell.</p>
      <p>The next major breakthrough in dermatologic research on PDT came in 1978, when Dougherty et al. [<xref ref-type="bibr" rid="ref8">8</xref>] described a new photosensitizer, which became known as hematoporphyrin purified derivative (HPD). HPD was a complex of porphyrin subunits and porphyrin by-products. The group successfully demonstrated that HPD could be successfully used to treat cutaneous malignancies with an appropriate light source, which in this case was a red light source. This was an extremely important contribution to the PDT literature, and systemic HPD became the standard for PDT for the next 10 years of PDT. A variety of medical uses emerged for PDT during this period of time, both oncologic and nononcologic, and some of the more common indications for PDT use in dermatology are shown in table <xref ref-type="table" rid="T01">1</xref>.</p>
      <p>
        <table-wrap position="float" id="T01">
          <label>Table 1</label>
          <caption>
            <p>Common uses of PDT in dermatology</p>
          </caption>
          <graphic xlink:href="http://www.karger.com/WebMaterial/ShowPic/492576" xmlns:xlink="http://www.w3.org/1999/xlink" />
        </table-wrap>
      </p>
      <p>The skin is a great resource for medical research, especially PDT research, since exposure to both natural and artificial light sources can be done with relative ease. Interest in PDT as a potential therapy for many skin concerns continued to grow with the use of HPD. However, because HPD remained phototoxic on the skin for several months as its precursor did, many did not favor its practical use. Then, in 1990, Kennedy et al. [<xref ref-type="bibr" rid="ref9">9</xref>] introduced the first topical porphyrin derivative and the face of PDT changed forever. This topical porphyrin derivative was 5-aminolevulinic acid (ALA), and this would be the photosensitizer that would become the standard for PDT to this day.</p>
      <p>ALA is known in medicine as a prodrug, which, when incorporated into a cell, is converted into its active drug form. Kennedy et al. [<xref ref-type="bibr" rid="ref9">9</xref>] found that topical ALA could penetrate through the skin's main barrier, the stratum corneum, and once past the barrier, be absorbed selectively by actinically damaged skin cells, which opened the door for dermatologists to potentially treat actinic keratoses, becoming more and more prevalent in our society. They also noted that the topically applied ALA was selectively absorbed into nonmelanoma skin cells and also into the pilosebaceous units of the skin. They first described the PDT reaction with ALA. Once incorporated into the skin, ALA, which is a prodrug, is absorbed through the stratum corneum, enters the specific cells that are in the area, whether actinically damaged skin cells or nonmelanoma skin cells, or the pilosebaceous units, and is converted into its active form, which is known as protoporphyrin IX (PpIX).</p>
      <p>In order to understand ALA and PpIX, one must look at the heme pathway, as shown in figure <xref ref-type="fig" rid="F01">1</xref>. ALA is the prodrug photosensitizing agent and PpIX is the actual photosensitizer. In order for the PDT reaction to be successful, the photosensitizer must be exposed to a light source with an appropriate wavelength that will interact with the photosensitizer. PpIX has been studied extensively with a variety of lasers and light sources over the past 35 years, and many of those devices will be described more in later chapters in this book. What should be noted here is that blue light has been the most studied light source in the United States, although many use blue light and other light sources routinely in their clinical practices.</p>
      <p>
        <fig position="float" id="F01">
          <label>Fig. 1</label>
          <caption>
            <p>The heme biosynthetic pathway. PpIX absorption in vivo (mouse skin). ALA is the natural precursor of PpIX in the heme pathway.</p>
          </caption>
          <graphic xlink:href="http://www.karger.com/WebMaterial/ShowPic/492575" xmlns:xlink="http://www.w3.org/1999/xlink" />
        </fig>
      </p>
      <p>The absorption spectrum of PpIX has been elucidated and is shown in figure <xref ref-type="fig" rid="F02">2</xref> with the various lasers and light sources that can successfully activate PpIX. The peak absorption bands noted are in the blue light range, and these peaks are known as the Soret bands. Smaller peaks are also noted in the red light range, which is also very important for dermatologic applications of PDT. In Europe, the methyl ester of ALA, commonly referred to as methyl aminolevulinate (MAL), is the most common photosensitizer that is currently used, and a great deal of research with MAL and red light has been performed and will be reviewed later.</p>
      <p>
        <fig position="float" id="F02">
          <label>Fig. 2</label>
          <caption>
            <p>The absorption spectrum of PpIX, and the lasers and light sources which have been shown to be useful in the activation of PpIX.</p>
          </caption>
          <graphic xlink:href="http://www.karger.com/WebMaterial/ShowPic/492574" xmlns:xlink="http://www.w3.org/1999/xlink" />
        </fig>
      </p>
      <p>When one looks at the absorption spectrum of PpIX, one also notices several smaller peaks between blue and red light. These peaks have become important for many as certain lasers and light sources have been shown to work within these peaks to activate ALA or MAL, and have helped expand the use of PDT as we move further into the 21st century, a long road traveled since 1900 and our first foray into PDT.</p>
      <p>One of the main advantages of using ALA or MAL for our current-day PDT use is that we have shortened tremendously the phototoxic reaction times of the drug on the skin. This has to do with the heme pathway, once again shown in figure <xref ref-type="fig" rid="F01">1</xref>. The heme biosynthetic pathway is maintained under a very close feedback loop system, which does not allow for the buildup of heme or any of its precursors, including PpIX in tissues. Exogenous ALA forming PpIX is cleared from the body much more rapidly than its predecessor HPD. Therefore, the potential for ALA to form a phototoxic skin reaction is considerably reduced as compared to HPD. We now note that this potential is only several days in most accounts as compared to the several months that were seen with HPD. And with the specificity that exists with ALA, this has become an ideal photosensitizer for dermatology.</p>
      <p>PDT has taken two separate pathways into our dermatologic clinics, and this is a result of the manufacturing and production process that has emerged in the PDT world. In the United States, we have focused our attention on topical ALA, which commercially is a 20% ALA solution known as Levulan® Kerastick™, manufactured by DUSA Pharmaceuticals (Wilmington, Mass., USA). The only FDA indication, which will be explained later, is for the treatment of nonhyperkeratotic actinic keratoses of the face and scalp using a blue light source. Many clinicians utilize Levulan® off-label for a variety of indications, including moderate-to-severe acne vulgaris, sebaceous gland hyperplasia, hidradenitis suppurativa, and for nonmelanoma superficial skin cancers.</p>
      <p>In Europe, research has centered primarily on MAL. It is commercially available as a 16.8% cream, known as Metvix®, from Galderma Laboratories (Fort Worth, Tex., USA). Its primary use in Europe has been in the treatment of nonmelanoma skin cancers with the use of red light as the main light source. Off-label, Metvix® has been used for the same indications as ALA in the United States [<xref ref-type="bibr" rid="ref10">10</xref>]. MAL did have FDA approval for the use in the treatment of actinic keratoses with red light in the United States, but was never widely used and is no longer available at the time of this writing on the US market.</p>
      <p>This textbook will explore PDT and its uses in dermatology today from a group of highly respected clinicians that have helped make PDT a common and an accepted form of therapy for our patients who benefit from our work. PDT is used and should be used daily in our dermatology practices, and we have gained much understanding of and insight into the past on how to best accomplish this. Looking ahead, we will continue to look at our photosensitizers and see if we can improve on them. We will continue to look at the light sources we use, and how we can maximize them, how we can combine them, and what the best approaches are when it comes to temperature and sunlight - whether daylight PDT has a significant role for us to consider moving forward. And as well, the concept of drug delivery is very important today, and how we can use lasers and light sources to help make the delivery of our photosensitizers better, all are under study, and will help shape the future of PDT for all of us.</p>
      <p>PDT has become a truly global therapeutic modality that affects lives. The hope of this textbook is to bring all of you together - some of the brightest minds in PDT from all over the world - to share the science that exists and learn from the experiences made, to make this the most up-to-date review on PDT yet, and my sincere thanks to all of them.</p>
    </sec>
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  <back>
    <ref-list>
      <title>References</title>
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        <label>1</label>
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        <mixed-citation>Gold MH, Goldman MP: 5-Aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg 2004;30:1077-1084.</mixed-citation>
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