To Heal The Skin Contents & Preface

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To Heal THe Skin

2L

inacre’s Books

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To Heal THe Skin The Heroes Behind Discoveries in Dermatology

W. STuarT Maddin, Md H. eileen Murray, Md Editors

2L

inacre’s Books

an imprint of Chronicle Companies

Buffalo, N.Y. USA • Toronto, ONT. Canada

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LINACRE’ S BOOKS Published by chronicle companies

chronicle Lifesci america corp.

Buffalo, new York, 14203, Usa

chronicle information resources Ltd. Toronto, ontario, canada 555 Burnhamthorpe road suite 306 Toronto, ont. M9c 2Y3 Tel. 866.63.cHron (866.632.4766) email: inquiry@tohealtheskin.com

www.tohealtheskin.com First north american edition published May 2015 copyright 2015 © Linacre's Books, An Imprint of Chronicle Companies

all rights reserved isBn 978-0-9685848-4-2 set in arno Pro, Gill sans and Franklin Gothic.

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For our patients. always know that you are the reason and the purpose behind the work described herein

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Contents Preface W. s T U a rT M a d d i n ..........................................................xi

Foreword H . e i L e e n M U r r aY ................. .........................................xv F

5-FU: Treatment of actinic keratoses L a r rY P a r i s H

and

M i c H e L e F a r B e r ..................................1

acyclovir: The First antiviral The Story of Gertrude B. Elion [Nobel Prize 1988] s T e P H e n T Y r i n G ..............................................................9

adapalene: a Less irritating Topical retinoid B r a H a M s H r o o T ..............................................................1 7

aloe Vera: Healing Plant Juice r aY M o n d d U F r e s n e , J r . ..............................................2 5

alpha-hydroxy acids: Fruit acids for smooth skin e U G e n e V a n s c o T T & r U e Y Y U ........................................3 3

Hurley-shelley Procedure J e F F e rY H U r L e Y ..............................................................4 3

arsenic: The silver Bullet for syphilis The story of Paul Ehrlich [Nobel Prize 1908] M a r i s a k a r d o s G a r s H i c k & k e n T s e P k o W i T z ................51

azaleic acid: For Both acne and rosacea M a U r o P i c a r d o .............................................................. 6 1

Benadryl: The First antihistamine P e T e r H U L L ............................ ........................................ 67

Benzoyl Peroxide: an effective Topical acne Medication The story of Bill Pace L Y n G U e n T H e r .............................................................. 7 1

Botox: neurotoxin smoothing the Brow a L a s Ta i r

and

J e a n c a r r U T H e r s ......................................7 7

calcineurin inhibitors: First effective non-steroidal Topical Medication for eczema a n d r e W L i n & c o n G W a n G .... ........................................ 87 vii

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To Heal THe Skin: The Heroes Behind Discoveries in Dermatology

calcipotriol: Topical Vitamin d for Psoriasis P o U L r a s M U s s e n .................... ........................................9 3

camouflage development: That Hides the difficult The story of Lydia O’Leary n e i L s H e a r .............................. ......................................101

cantharidin: Gets rid of Warts, and More M a rY c H a n G .......................... ......................................1 0 9

chemical Peel: Quite Beyond the “Paris Peelers” G a rY M o n H e i T ........................ ......................................1 15

chloroquine: For cutaneous Lupus erythematosus c a M i L L e F r a n c è s .................... ......................................121

corticosteroids (Hydrocortisone): The Versatile anti-inflammatory The story of Dr. Marion Sulzberger s T U a rT M a d d i n ............................................................12 7

crude coal Tar: The First effective Topical for Psoriasis The Goeckerman story r o B e rT J a c k s o n .................... ......................................135

cryosurgery: The story of dr. Gloria Graham s a r a M o r a d i T U c H aY i , V i r G i n i a c o n n o L LY W a L k e r & s T e V e n r . F e L d M a n ............ ......................................1 41

dapsone: Benefits Leprosy and dermatitis Herpetiformis P r o F . G o T T F r i e d W o z e L ........ ......................................1 4 9

dermabrasion: smoothing acne scars M U r a d a L a M .......................... ......................................1 5 5

electrosurgery: Bloodless surgery The story of William T. Bovie’s machine used by Dr. Harvey Cushing, s H e L d o n P o L L a c k .................. ...................................... 1 61

Fillers: re-defining Facial contours r i c H a r d G L o G a U .................... ...................................... 16 9

Finsen Light: Ultraviolet Light Treatment The Niels Ryberg Finsen story [Nobel Prize 1903] s U n i L k a L i a & z a F i r d a M a n i .. ......................................17 7

Fusidic acid: Topical anti-bacterial Workhorse P o U L r a s M U s s e n .................... ...................................... 18 3

Griseofulvin: The First oral antifungal Medication Discoverer, Harald Rastrick [Nobel Prize]; Researchers, Dr. James Gentles, Dr. Harvey Blank a d i T Ya G U P Ta & d e a n n e d a i G L e ..................................18 9 viii

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CONTENTS

Hair Transplants The Story of Norman Orentreich as told by his son d aV i d s. o r e n T r e i c H ............ ......................................1 95

Hydroquinone: Bleaching the skin J a M e s n o r d L U n d ..........................................................203

immunomodulators: kick-starting the Body’s immune system r i c H a r d M i L L e r ..........................................................209

ingenol Mebutate: a Botanical for ak P e T e r W e L B U r n ............................................................21 5

isotretinoin: The Gold standard for Treating acne G a rY P e c k .............................. ......................................225

Lasers: Magic With Light r o x a n d e r s o n ............................................................23 7

Methotrexate: First for r.a., and Then Psoriasis J a n d U T z ......................................................................24 5

Topical Minoxidil: a Treatment for Male Pattern Baldness r i c H a r d L . d e V i L L e z ....................................................255

Mohs: Micrographic surgery s T e P H e n s n o W & P a U L L a r s o n ......................................26 1

niacin: Vitamins and the skin d o U G L a s L a n s k a ..........................................................267

oral azole antifungals The story of Paul Janssen G e e rT c a U W e n B e r G H ....................................................277

Patch Testing: diagnosing allergic contact dermatitis M e L a n i e P r aT T & B r a n d o n W o r L e Y ............................28 3

PdT: a Unique Treatment approach Pioneered by Two canadian scientists James Kennedy and Roy Pottier J a G G i r a o .............................. ...................................... 2 9 1

Penicillin: The antibiotic That Tamed syphilis The story of John Mahoney told by his daughter and son J a n e T M a H o n e Y & J o H n M a H o n e Y ..............................2 99

Phlebology-sclerosing Veins d aV i d d U F F Y .......................... ...................................... 3 07

Podophylotoxin: another Botanical agent for the skin s c o T T n o rTo n ........................ ...................................... 3 1 5 ix

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To Heal THe Skin: The Heroes Behind Discoveries in Dermatology

Propranolol: shrinking infantile Hemangiomas c H r i s T i n e L a B r è z e & a L a i n T a ï e B ................................3 23

P UVa: Psoralen plus UVa J o H n a . P a r r i s H ............................................................32 9

sulfur for scabies M a r i a H i c k s .......................... ......................................3 3 7

sunscreens: an addition That Has Made a difference J a s o n r i V e r s .......................... ......................................3 4 1

Tazarotene: a retinoid That Helps acne and Psoriasis The chemist who invented it tells his story r o s H c H a n d r a r aT n a ............ ......................................3 49

Thalidomide: dr. Jacob sheskin and the rediscovery of a reviled drug V i c To r i a P. W e rT H & J a M i e L a n G e n H a n ......................3 55

Tretinoin: The Prime Topical retinoid H a r a L d G o L L n i c k .................. ......................................36 3

Urea: although Present in Urine Benefits the skin o L L e L a r k o ............................ ......................................369 F

afterword M i Tc H e L L s H a n n o n ......................................................37 5

contributors to This Book ....................................................384 about the editors .......................... ......................................3 9 5

x

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PREFACE

W. Stuart Maddin,

MD, FRCPC VA N CO U V E R , B R I T I S H CO LU M B I A , C A N A DA

THIS BOOK BEGINS where i began: in the drugstore owned by my father in cupar, saskatchewan, back in the mid- to late 1920s. i was a small child, glimpsing those dignified displays of intriguingly packaged medicinal salves and potions and ointments and compounds and preparations, through the eyes of a child.

How i wondered about them, then.

What were those objects? People would come in, anxiously, it seemed to me, and leave the store with a white paper bag containing one of those tubes, or jars, or small boxes.

They would return later, and i would observe them thanking the pharmacist—who happened to be my father, Max—for the relief those products had provided. and the little boy that i was pondered: What were those medicines?

Where did they come from? i grew up, and left cupar, went to medical school back east, and then xi

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did postgraduate training at new York skin and cancer Hospital. My classmates and i learned a fair bit about therapeutic agents and products. The information was contained in documents known as monographs. Pharmacopoeia, they called it.

Those monographs told you all you would ever want to know about chemical composition, and method of action, and contraindications, and what-not. But, as dermatology resident, i was consistently unable to fathom why nothing was ever said about the investigator. surely, i thought, there was someone behind the product. There must have been a guy, or a gal, or a team, who figured it out, took it from lab to dispensing table. certainly, i reasoned, some driven person shepherded these remedies from the moment of creative spark, through the final obstacles of regulatory approval.

How does any of this does this occur?, i wondered.

That aspect of therapeutics was never discussed in med school, and has been infrequently mentioned thereafter, during the seventy years that have transpired since i graduated.

That seems odd. of the medicines outlined in the Table of contents of this book, be aware that hundreds of millions of people use these products each and every day. nonetheless, it’s a fact that physicians and residents, pharmacists, patients and the public at large don’t often show very much curiosity about the genesis of the therapies we commonly use. it’s also a fact that behind every significant drug discovery you will find a minimum of several fascinating stories.

For my part, my child-like curiosity concerning the hows and whys of these innovations has only intensified over the years.

The purpose of this book is to take some of the major treatment agents and find out from the investigators (or their descendants, or their collaborators) as much as possible. Who struck upon the concept? How was it done? What were the hurdles? and, most tellingly, who were the individuals behind these discoveries? Where did they go to school? How did they happen to become involved in dermatology? What is their personal story? i wanted to identify these people, to regard them as the admirable xii

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PREFACE • Maddin

figures they are, and make them and their stories come alive. i have been fortunate enough to personally know several of the noble folks featured and i’ve watched with fascination the process that they went through.

There is an aversion in medicine toward aggrandizement. Many consider it unseemly to elevate the accomplishments of a colleague or peer, especially in a collaborative area, such as drug discovery. However, i will argue that there is a perfectly good word available to describe an individual or group whose efforts and actions have contributed toward ameliorating the suffering and discomfort of our fellow humans. That word, which has been around for 638 years, is Hero. it comes from the Greek ἥρως, which translates as “protector.” That’s perfect. i’ll therefore propose that the next time you apply a product to your skin for the purpose of avoiding the harmful effects of the sun, or to bring relief to your rash or inflamed plaque psoriasis, or to correct the distressing effects of aging, or to deal with (as i have personally dealt with very recently) the potentially life-threatening matter of actinic keratoses, perhaps you might give a thought to those who endeavored to protect you from the unhappy consequences of disease, poor luck, and occasionally inadvisable behavior. nearly one hundred years ago, the industrialist Henry Ford gave an interview to the chicago Tribune, during the course of which he famously opined, “History is more or less bunk. it’s tradition. We don’t want tradition. We want to live in the present and the only history that is worth a tinker’s dam is the history we made today.”

Be that as it may, time passes. a full century later, in our current age of iT-enabled ephemera such as Twitter, Facebook, snapchat, and so on, the term “history” has managed to remain just as unfashionable as when Ford denounced it. Yet, history is made, and keeps on being made, by people whose focus is not on posterity, but simply on figuring out small practical improvements where it seems possible to do so, whose desire is not to earn a spot in historic annals, but to make something happen, to get something done.

My small contribution toward that general impulse is to compile this xiii

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volume, in time for the 23rd World congress of dermatology, to be held in my hometown of Vancouver in 2015. i would like to especially thank my collaborators—eileen Murray and Mitch shannon —without whom this book would not have been possible, and whose editing, writing contributions, and time committed cannot be underestimated.

xiv

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FOREWORD

H. Eileen Murray,

MD, FRCPC VA N CO U V E R , B R I T I S H CO LU M B I A , C A N A DA

WE HAVE COLLECTED HERE stories of heroes: Heroes who worked and studied to discover how to improve and make a difference in the lives of patients with skin diseases. as was true of the geographic and cultural explorations of past millenia, which revealed new worlds, none of these medical discoveries has been easy, or come without cost.

The dermatologic explorers of more recent time had to endure disbelief, suffer the skepticism of colleagues, work around a lack of space, survive past the withdrawal of funds—and go on to test hundreds, sometimes thousands, of molecules.

What do the researchers described in this book have in common?

The common factors seem to be: Unwavering self-belief, boundless determination and tenacity, along with good luck and occasional serendipity.

They cared enough to start again, they did not falter or give up. They found a way in spite of sometimes incredible odds to succeed. (Many are xv

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gracious enough to credit wonderful parents and teachers, who instilled the love, joy and excitement of learning, good friends, supportive colleagues, encouraging mentors and helpful spouses.) You will find something to inspire, in each of these stories.

We have included stories of inventions of procedures as well as the invention of drugs, including the beginnings of patch testing, electrosurgery and phlebology. The use of light therapy began with Finsen; applications of light including PUVa, lasers and photodynamic therapy followed. surgical advances have been nothing short of amazing. These include hair transplants, cryotherapy, dermabrasion and Mohs micrographic surgery. chemical peels have been used for centuries. now we have safer peels, as well as fillers and toxins. some ancient medicines, including coal tar, sulfur, cantheridin, and podophyllotoxin are still used, but with added safety, due to a greater understanding of their benefits and risks. several therapies were rescued from obscurity, which makes for fascinating story-telling. so-called “natural products” seem to be society’s current rage. aloe vera was one of the spices used by ancients for embalming, and is still cultivated in huge quantities for medicinal products and as an additive in cosmetics. The isolation of the alpha hydroxy acids from grapes, sugar cane and sour milk, was determined to be of great benefit to those with hereditary ichthyosis, and all of us with sun-damaged skin. Today’s formulations are modern, and concentrated, but the underlying therapeutic agent has smoothed complexions for thousands of years. (one early “celebrity endorser” was none other than the last active pharaoh of ancient egypt, cleopatra.)

Medicinal uses for vitamins have been sought for years. researchers from Japan, europe and north america have now provided us with derivatives of vitamins a and d that safely provide remarkable benefits for those with acne and psoriasis. it took a long time to recognize vitamin-deficiency diseases. We have included the story of pellagra and the discovery of its cause—vitamin B3 (niacin) deficiency. its amide form (niacinamide) is used to treat some inflammatory skin diseases, such as bullous pemxvi

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FOREWORD • Murra y

phigoid. additionally, it is now being added to cosmetics. since much of this book deals with pharmaceutical agents, a reasonable starting question for that category of therapies might be: Where did the search for drugs begin?

The answer is improbable. drugs came through, of all things, people’s urge to dye their clothes. Germany had a substantial dye industry in the 19th century, and researchers began to use the dyes to stain intracellular structures and bacteria. noting that each dye would adhere to a specific structure in the cell, Paul ehrlich imagined a magic bullet. This idea led him to try to find a dye that adhered and killed the spirochetes that caused syphilis. compound number 606 arsphenamine worked, and became the standard treatment of syphilis until penicillin became available. other antibiotics derived from dyes followed, including dapsone and the red dyestuff (prontosil rubrum), the first sulfonamide used to treat infections. after penicillin was isolated from a mould that killed bacteria, chemical isolates from thousands of moulds and bacteria found in soil samples from everywhere have been tested. The drugs produced have benefited humankind and include, the antifungal griseofulvin, numerous antibiotics, and also the calcineurin inhibitors.

The fungus that produced cyclosporin, the first calcineurin inhibitor, was found in a handful of norwegian dirt taken from above the arctic circle in 1969. Marcella Porro-nazzaro discovered azelaic acid in the fungus, pitirosporum, that grows on human skin. once a chemical was discovered, chemists modified and reinvented it in order to find new active ones that would be safer and more effective.

Benadryl was first usable antihistamine. We now have numerous azole antifungal medications. Tazarotene was one of a hundred retinoic analogues. of course, serendipity and garden-variety luck also have had a role in many discoveries. Bald patients noticed, with approval, their hair growing back when treated for high blood pressure with oral minoxidil. When Gary Peck wanted a retinoid to test, the only retinoid available when he called the supplier was isotretinoin, which he determined to be the only oral retinoid efficacious for acne. in 1964, dr. Jacob sheskin needed a sedative other than a barbiturate for a patient near death with severe erythema xvii

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nodosum leprosum. He found an old bottle of thalidomide in the hospital infirmary, and gave the patient two tablets. With continued treatment, the patient’s skin recovered completely, to dr. sheskin’s considerable amazement.

These are just a few excerpts from the many wonderful stories. The authors of the chapters which follow have exceeded all our expectations, searching old records, and spending precious hours to honour each hero.

We are extremely grateful to each and every one of them for their efforts.

ACKNOWLEDGEMENTS We are also immensely grateful for the help of three exceptional librarians from the British columbia college of Physicians and surgeons, who found contact information for family members and who found obscure and ancient historical documents, which made our heroes come alive. To Carrie Grinstead, Karen MacDonell and Scott Anderson our most grateful thanks.

We also wish to thank those family members who provided us with information, photos and stories. a special thank you to Dr. David Gratton who provided us with an english summary of a 28- page document in ancient French about the life and work of the Belgian physician dr. Jean-Francois Vleminckx. it has been my good fortune that dr. stuart Maddin gave me the chance to participate in this amazing project, mentored me, and has become a treasured and wonderful friend. xviii