ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
`Volume 544
`
`ANTIFUNGAL DRUGS
`
`Edited by Vassil St. Georgiev
`
`The New York Academy of Sciences
`New York, New York
`1988
`
`Page 1 of 26
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1514
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`

`

`AWAL
`
`Copyright © 1988 by the New York Academy of Sciences. All rights reserved. Under the provisions
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`@ The paper used in this publication meets the minimum requirements of American National
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`
`Library of Congress Cataloging-in-Publication Data
`
`Antifungal drugs/edited by Vassil St. Georgiev.
`
`p. cm.—(Annals of the New York Academy of Sciences,
`ISSN 0077-8923; v. 544)
`Contributions presented at the First International
`Conference on Drug Research in Immunologic and
`Infectious Diseases, held in Garden City, N.Y., on Oct.
`8-10, 1987 and sponsored by the New York Academy of
`Sciences.
`Includes bibliographies and index.
`ISBN 0-89766-510-4 (alk. paper).-ISBN 0-89766-511-2
`(pbk.: alk. paper)
`1. Antifungal agents—Congresses. 2. Mycoses—
`Chemotherapy—Evaluation—Congresses. I. Georgiev,
`Vassil St. II. International Conference on Drug Research in
`Immunologic and Infectious Diseases (1st: 1987: Garden
`City, N.Y.) III. New York Academy of Sciences. IV.
`Series.
`[DNLM: 1. Antifungal Agents—congresses. 2. Fungi
`—drug effects—congresses. 3. Mycoses—drug therapy
`—congresses. W1 AN626YL v. 544/QV 252 A629 1987]
`Q11.N5 vol. 544
`[RM410]
`500 s-dc 19
`[616.9'69061]
`DNLM/DLC
`for Library of Congress
`
`88-38918
`CIP
`
`PCP
`Printed in the United States of America
`ISBN 0-89766-510-4 (cloth)
`ISBN 0-89766-511-2 (paper)
`ISSN 0077-8923
`
`QI
`
`IN
`
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`V/.Siflf
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`B/oL
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`
`Page 2 of 26
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`

`

`ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
`
`Volume 544
`December 14, 1988
`ANTIFUNGAL DRUGS"
`
`Editor and Conference Chairman
`Va s s il St . Ge o r g ie v
`Conference Cochairmen
`Hid e y o Ya ma g u c h i and C. Ric h a r d Kin s o l v in g
`Session Chairs
`Jo h n E. Be n n e t t , Je r o me Bir n b a u m, Da v id J. Dr u t z , Ma r v in Go r ma n ,
`Ar n o l d L. Le n t n e k , and Din u Ra n e
`
`CONTENTS
`
`Fungal Infections and the Search for Novel Antifungal Agents:
`Opening Remarks. By Va s s il St . Ge o r g ie v .............................. 1
`
`Part I. Design, Synthesis, and Structure-Activity Relationships of
`Antifungal Agents
`Design and Evaluation of a Systemically Active Agent, Fluconazole.
`By K. Ric h a r d s o n , K. Co o pe r , M. S. Ma r r io t t , M. H.
`Ta r b it , P. F. Tr o k e, and P. J. Wh it t l e ..................................... 4
`Synthesis of Antifungal Imidazoles and Triazoles. By Ma s a r u
`Og a t a ............................................................................................ 12
`Synthesis and Antifungal Activity of Novel Isoxazolidine
`Compounds. By Ge o r g e B. Mu l l e n , Pa t r ic ia A. Sw if t ,
`Gr a c e A. Be n n e t t , Th o ma s R. De Co r y , Da v id M.
`Ma r y n ia k , Pe t e r G. Do r me r , and Va s s il St . Ge o r g ie v ... 32
`Synthesis and Structure-Activity Correlations within Allylamine
`Antimycotics. By An t o n St u t z .................................................. 46
`Structure-Activity Relationships of 2-(l.^-Imidazol-l-yl)vinyl
`Ethers: Route to the New Broad-Spectrum Antifungal Agent
`Omoconazole. By L. Zir n g ib l , J. Fis c h e r , U. Ja h n , and
`K. Th ie l e ......................................................................................... 63
`
`"All of the contributions to this volume were presented at the First International Conference
`on Drug Research in Immunologic and Infectious Diseases. Antifungal Drugs: Synthesis, Pre-
`clinical and Clinical Evaluation. The conference, which was sponsored by the New York Academy
`of Sciences, was held in Garden City, New York, on October 8-10, 1987.
`
`Page 3 of 26
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`Vibunazole and Its Enantiomers: Synthesis, Antifungal Activity,
`and Pharmacokinetics. By Wo l f g a n g Rit t e r , Gr a h a m
`Ho l mw o o d , Ha n s-Ju e r g e n Ah r , Kl a u s De t z e r , Ud o
`Kr a a t z, Ma n f r e d Pl e mpe l , Die t r ic h Sc h e r l in g , and
`Ha n s-Ma r t in Sie f e r t ................................................................. 74
`Synthesis and Structure-Activity Relationships of a Novel
`Antifungal Agent, ICI 195,739. By F. Th o ma s Bo y l e, Da v id
`J. Gil ma n , Mic h a e l B. Gr a v e s t o c k , and J. Mic h a e l
`Wa r d l e w o r t h ............................................................................ 86
`Pyrido[3,4-e]-l,2,4-triazines and Related Heterocycles as Potential
`Antifungal Agents. By M. F. Re ic h , P. F. Fa b io , V. J. Le e ,
`N. A. Ku c k , and R. T. Te s t a .................................................. 101
`Synthesis and Antifungal Properties of Dihydrobenzothiophene
`Azoles. By D. F. Ra n e , J. A. De s a i, D. Lo e b e n b e r g , R.
`Pa r me g ia n i, and R. E. Pik e ...................................................... 105
`Synthesis and Antifungal Properties of 14-Aminomethyl-Substituted
`Lanosterol Derivatives. By A. B. Co o pe r , J. J. Wr ig h t , A. K.
`Ga n g u l y , J. De s a i, D. Lo e b e n b e r g , R. Pa r me g ia n i, and
`D. S. Fe in g o l d ............................................................................. 109
`
`Part II. Structural Elucidation, Synthesis, and Antifungal Activity of
`Natural Products and Related Derivatives
`Antifungal Substances from Marine Invertebrates. By No b u h ir o
`Fu s e t a n i...................................................................................... 113
`The Galbonolides: Novel, Powerful Antifungal Macrolides from
`Streptomyces galbus ssp. eurythermus. By Ha n s Ac h e n b a c h ,
`An d r e a s Mu h l e n f e l d , Ur s u l a Fa u t h , and Ha n s
`Za h n e r ......................................................................................... 128
`Antifungal Proteins from Plants. By Wa l d e n K. Ro b e r t s,
`Br id g e t E. La u e , and Cl a u d e P. Se l it r e n n ik o f f ............... 141
`Synthesis and Evaluation of LY121019, a Member of a Series of
`Semisynthetic Analogues of the Antifungal Lipopeptide
`Echinocandin B. By M. De b o n o , B. J. Ab b o t t , J. R.
`Tu r n e r , L. C. Ho w a r d , R. S. Go r d e e, A. S. Hu n t , M.
`Ba r n h a r t , R. M. Mo l l o y , K. E. Wil l a r d , D. Fu k u d a ,
`T. F. Bu t l e r , and D. J. Ze c k n e r ............................................. 152
`Amphotericin B: Synthesis of Its Aglycone (Amphoteronolide B)
`and Degradation. By Sa t o r u Ma s a mu n e ................................... 168
`Hydroxamic Acid Antimycotic Antibiotics: A New Group of
`Antibiotics. By Yo s h io In o u y e, Hir o ma s a Ok a d a , and
`Sh o s h ir o Na k a mu r a .................................................................. 180
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`Page 4 of 26
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`L-660,631, a New Antifungal Agent. By A. J. Ke mpf , O. D.
`He n s e n s, R. E. Sc h w a r t z, R. S. Sy k e s, K. E. Wil s o n , C.
`F. WicHMANN, D. L. Zin k , L. Zit a n o , and S. Mo c h a l e s ....
`Novel Antifungal Antibiotic BMY-28567: Structural Study and
`Biological Activities. By To s h ik a z u Ok i, Ky o ic h ir o Sa it o h ,
`Kozo To ma t s u , Ko ji To mit a , Ma s a t a k a Ko n is h i, and
`Hir o s h i Ka w a g u c h i.................................................................. 184
`RI-331, a New Antifungal Antibiotic. By Hid e y o Ya ma g u c h i,
`Ka t s u h is a Uc h id a , Ta mio Hir a t a n i, Ta k a t o s h i Na g a t e ,
`Na o h a r u Wa t a n a b e, and Sa d a t o s h i Omu r a ....................... 188
`
`183
`
`Part III. Biochemical Studies and Mechanism of Action of Antifungal
`Agents
`Mode of Action Studies: Basis for the Search of New Antifungal
`Drugs. By Hu g o Va n d e n Bo s s c h e, Pa t r ic k Ma r ic h a l , Jo s
`Go r r e n s, Hu g o Ge e r t s , and Pa u l A. J. Ja n s s e n .................. 191
`Mechanism of Action and Biochemical Selectivity of Allylamine
`Antimycotic Agents. By Ne il S. Ry d e r ..................................... 208
`Mode of Action of Morpholine Derivatives. By An n e ma r ie Po l a k 221
`Mode of Action of L-660,631 in Candida albicans. By Ja n e t C.
`On is h i, Ge o r g e K. Ab r u z z o , Ro b e r t A. Fr o mt l in g ,
`Ge o r g e M. Ga r r it y , Ja me s A. Mil l ig a n , Ba r b a r a A.
`Pe l a k , and Wa l t e r Ro z d il s k y ................................................ 229
`Mode of Action of ;8-Lactone 1233A in Candida albicans. By
`Ja n e t C. On is h i, Ge o r g e K. Ab r u z z o , Ro b e r t A.
`Fr o mt l in g , Ge o r g e M. Ga r r it y , Ja me s A. Mil l ig a n ,
`Ba r b a r a A. Pe l a k , Wa l t e r Ro z d il s k y , and Ba r b a r a
`W EISSBERGER......................................................................... 230
`Biochemical Studies with a Novel Antifungal Agent, ICI 195,739.
`By Ke it h Ba r r e t t -Be e , Jo y c e Le e s , Ph il ip Pin d e r , Ju l ie
`Ca mpb e l l , and Lo r r a in e Ne w b o u l t ..................................... 231
`Drug Resistance in Candida albicans and Candida glabrata. By
`Da v id Ke r r id g e , Ma r c o Fa s o l i, and Fr a n c e s J.
`Wa y ma n ....................................................................................... 245
`Isolation and Characterization of Fluoropyrimidine-Resistant
`Mutants in Two Candida Species. By Ma r c o Fa s o l i and
`Da v id Ke r r id g e ........................................................................ 260
`
`Part IV. Preclinical Evaluation of Antifungal Agents
`Role of Animal and Human Pharmacology in Antifungal Drug
`Design. By Ge e r t Ca u w e n b e r g h and Ja n Va n Cu t s e m ....
`
`264
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`Page 5 of 26
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`310
`
`Use of Chemiluminescence to Evaluate the Influence of Antifungal
`Agents on Immune Cell Function. By Ro b e r t A. Fr o mt l in g ,
`Ge o r g e K. Ab r u z z o , Tr a c y A. Tu r n b u l l , Da v id M.
`Gil t in a n , and Th o ma s P. Ca piz z i........................................... 270
`In Vitro Potency and in Vivo Activity of Azoles. By Pe t e r F.
`Tr o k e, Mic h a e l S. Ma r r io t t , Ke n n e t h Ric h a r d s o n , and
`Mic h a e l H. Ta r b it .................................................................... 284
`Axiti-Candida Activity and Toxicology of LY121019, a Novel
`Semisynthetic Polypeptide Antifungal Antibiotic. By Ro b e r t
`S. Go r d e e, Do u g l a s J. Ze c k n e r , Le o n a r d C. Ho w a r d ,
`Wil l ia m E. Al b o r n , Jr ., and Ma n u e l De b o n o ................... 294
`Activity of ICI 195,739—a Novel, Orally Active Bistriazole—in
`Rodent Models of Fungal and Protozoal Infections. By Jo h n
`F. Ry l e y , Sa n d r a Mc Gr e g o r , and Ro b e r t G. Wil s o n ......
`Evaluation of Fungicidal Action in Vitro and in a Skin Model
`Considering the Influence of Penetration Kinetics of Various
`Standard Antimycotics. By H. Ha n e l , W. Ra e t h e r , and W.
`Dit t ma r ........................................................................................ 329
`Sterol Biosynthesis Inhibitors: Secondary Effects and Enhanced in
`Vivo Efficacy. By Die t e r Be r g , Ma n f r e d Pl e mpe l , Ka r l -
`h e in z BiiCHEL, Gr a h a m Ho l mw o o d , and Kl a u s St r o e c h 338
`Activity of Triazole Derivatives against Pityrosporum orbiculare in
`Vitro and in Vivo. By Ja n Fa e r g e ma n n .................................... 348
`Direct Fungicidal Action of Tioconazole. By Wil l ia m H. Be g g s ...
`354
`Synergistic Effects of Ketoconazole and SF-86327 on the
`Proliferation of Epimastigotes and Amastigotes of Trypanosoma
`(Schizotrypanum) cruzi. By Ju l io A. Ur b in a , Ke y l a
`La z a r d i, Gis e l a La r r a l d e , Ta n ia Ag u ir r e , Ma r t a M.
`PiRAS, and Ro ma n o Pir a s.......................................................... 357
`Substituted 5-Phenoxyalkyl-3-phenyl-3-( l.ff-imidazol-l-ylmethyl)-2-
`methylisoxazolidines; Antifungal Activity and
`Structure-Activity Relationship Studies. By Ge o r g e B.
`Mu l l e n , Da v id M. Ma r y n ia k , Pa t r ic ia A. Sw if t ,
`St a n l e y D. Al l e n , Je f f r e y T. Mit c h e l l , C. Ric h a r d
`Kin s o l v in g , and Va s s il St . Ge o r g ie v .................................... 359
`In Vitro Antifungal Activity of Novel Substituted 3,5-Diphenyl-3-
`(lif-imidazol-l-ylmethyl)-2-methylisoxazolidine Derivatives. By
`Th o ma s R. De Co r y , Ge o r g e B. Mu l l e n , Je f f r e y T.
`Mit c h e l l , St a n l e y D. Al l e n , C. Ric h a r d Kin s o l v in g ,
`and Va s s il St . Ge o r g ie v .......................................................... 363
`cis-3-(Substituted phenyl)-3-(l^f-imidazol-l-ylmethyl)-2-methyl-5-
`([(substituted phenyl)thio(or amino)]methyl}isoxazolidines: In
`Vitro Antifungal Activity and Structure-Activity Relationships.
`By Th o ma s R. De Co r y , Pa t r ic ia A. Sw if t , Ge o r g e B.
`
`Page 6 of 26
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`Mu l l e n , Je f f r e y T. Mit c h e l l , St a n l e y D. Al l e n , C.
`Ric h a r d Kin s o l v in g , and Va s s il St . Ge o r g ie v .................. 366
`3-( Substituted phenyl)-3-( \H-1,2,4-triazol-1 -ylmethyl )-2-methyl-5-
`[(substituted phenoxy)methyl]isoxazolidine Derivatives:
`Structure-Activity Relationships. By Gr a c e A. Be n n e t t ,
`Pa t r ic ia A. Sw if t , Ge o r g e B. Mu l l e n , St a n l e y D.
`Al l e n , Je f f r e y T. Mit c h e l l , C. Ric h a r d Kin s o l v in g ,
`and Va s s il St . Ge o r g ie v .......................................................... 369
`c«-5-Alkoxyalkyl-3-phenyl-3-( 1 JT-imidazol-1 -ylmethyl )-2-
`methylisoxazolidine Derivatives. By Da v id M. Ma r y n ia k ,
`Ge o r g e B. Mu l l e n , Je f f r e y T. Mit c h e l l , St a n l e y D.
`Al l e n , C. Ric h a r d Kin s o l v in g , and Va s s il St . Ge o r g ie v 373
`In Vitro Antifungal Activity of Novel Substituted 3,5-Diphenyl-3-
`(1H-1,2,4-triazol-1 -ylmethyl)-2-methylisoxazolidine Derivatives.
`By Gr a c e A. Be n n e t t , Pa t r ic ia A. Sw if t , Ge o r g e B.
`Mu l l e n , Je f f r e y T. Mit c h e l l , St a n l e y D. Al l e n , C.
`Ric h a r d Kin s o l v in g , and Va s s il St . Ge o r g ie v ................... 375
`In Vitro Antifungal Activity and Structure-Activity Relationship
`Studies of Novel cis-5-Acyloxyalkyl-3-phenyl-3-(l.ff-imidazol-l-
`ylmethyl)-2-methylisoxazolidine Derivatives. By Da v id M.
`Ma r y n ia k , Ge o r g e B. Mu l l e n , St a n l e y D. Al l e n ,
`Je f f r e y T. Mit c h e l l , C. Ric h a r d Kin s o l v in g , and Va s s il
`St . Ge o r g ie v ................................................................................... 378
`c/s-5-Alkyl(or alkenyl)-3-phenyl-3-( l/f-imidazol-l-ylmethyl)-2-
`methylisoxazolidine Derivatives: In Vitro Antifungal Activity
`and Structure-Activity Relationships. By Pa t r ic ia A. Sw if t ,
`Gr a c e A. Be n n e t t , Ge o r g e B. Mu l l e n , Je f f r e y T.
`Mit c h e l l , St a n l e y D. Al l e n , C. Ric h a r d Kin s o l v in g ,
`and Va s s il St . Ge o r g ie v ............................................................. 381
`Novel 5-Phenyl(or phenoxyalkyl)-3-(2-furanyl)-3-(lif-imidazol-l-
`ylmethyl)-2-methylisoxazolidines: In Vitro Antifungal Activity.
`By Gr a c e A. Be n n e t t , Ge o r g e B. Mu l l e n , Je f f r e y T.
`Mit c h e l l , St a n l e y D. Al l e n , C. Ric h a r d Kin s o l v in g ,
`and Va s s il St . Ge o r g ie v .................................................... 384
`Comparisons of Ketoconazole, PR 969-566, PR 967-234, and PR
`967-248 as Antifungals in Vitro and in the Rat Model of
`Candidal Vaginitis based on Efficacy/Safety Profiles. By Ge n e
`C. Pa l me r , J. Ma r k Or d y , Ro y D. Simmo n s, Ja me s C.
`St r a n d , Ge o r g e B. Mu l l e n , C. Ric h a r d Kin s o l v in g ,
`Va s s il St . Ge o r g ie v , and St a n l e y D. Al l e n ........................ 387
`In Vitro Activity of Novel 5-( Phenyl or phenoxyalkyl)-3-(2-
`thienyl)-3-(l.ff-imidazol-l-ylmethyl)-2-methylisoxazolidines. By
`Ge o r g e B. Mu l l e n , Je f f r e y T. Mit c h e l l , St a n l e y D.
`Al l e n , and Va s s il St . Ge o r g ie v .............................................. 392
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`Page 7 of 26
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`In Vitro Activity of Novel 5-Carbonyl Derivatives of 3-Phenyl-3-
`(l^-imidazol-l-ylmethyl)-2-methylisoxazolidines. By Gr a c e A.
`Be n n e t t , Ge o r g e B. Mu l l e n , Th o ma s R. De Co r y ,
`St a n l e y D. Al l e n , Je f f r e y T. Mit c h e l l , and Va s s il St .
`Ge o r g ie v ......................................................................................... 396
`In Vitro Activity of Novel m-5-Substituted-3-(2-naphthalenyl)-3-
`(l.ff^-imidazol-l-ylmethyl)-2-methylisoxazolidine Derivatives. By
`Gr a c e A. Be n n e t t , Ge o r g e B. Mu l l e n , St a n l e y D.
`Al l e n , Je f f r e y T. Mit c h e l l , and Va s s il St . Ge o r g ie v .... 400
`Enhancement of Phagocytosis and Intracellular Killing of Candida
`albicans by Human Neutrophils in the Presence of a
`Morpholine Antifungal Derivative, Ro 14-4767. By M. D.
`Ric h a r d s o n and C. A. Gr a y .................................................... 403
`Antifungal Chemotherapy with Oral Amphotericin B. By Hid e y o
`Ya ma g u c h i, Ka t s u h is a Uc h id a , Ak io Ur a b e, and
`Fu mima r o Ta k a k u ..................................................................... 406
`Interferon Protects Mice against an Extracellular Infection of
`Aspergillus fumigatus. By R. N. Ta n d o n , A.-R. Fe u il l e t t e ,
`G. Ma h o u y , G. Ba d il l e t , R. M. Fr ie d ma n , and R. K.
`Ma h e s h w a r i................................................................................... 409
`Inhibition of Candida Species with a Eugenol-Thymol Iodide
`Mixture. By Wil l ia m R. Ho d g e and Cipr ia n o Ro d a s ...........
`
`412
`
`Part V. Pharmacokinetics of Antifungal Agents
`Pharmacokinetics of Antimycotics with Emphasis on Local
`Treatment. Ul r ic h Ta u b e r ..................................................... 414
`Steady State Parenteral Kinetics of Fluconazole in Man. By
`G. Fo u l d s, C. Wa js z c z u k , D. J. We id l e r , D. C. Ga r g ,
`and P. Gib s o n .............................................................................. 427
`
`Part VI. Clinical Evaluation of Antifungal Drugs
`Fungal Infections in Cancer Patients. By Ge r a l d P. Bo d e y ...........
`Life-Threatening Opportunistic Fungal Infection in Patients with
`the Acquired Immunodeficiency Syndrome. By Do n a l d
`Ar ms t r o n g ................................................................................... 443
`Treatment of Mycoses with Itraconazole. By Ric h a r d M. Tu c k e r ,
`Pa u l L. Wil l ia ms, Ed u a r d o G. Ar a t h o o n , and Da v id A.
`St e v e n s ......................................................................................... 45 j
`Chronic Mucocutaneous Candidiasis: Antibiotic and Immunologic
`Therapy. By Ch a r l e s H. Kir k pa t r ic k ....................................... 471
`Treatment of Coccidioidomycosis. By Jo h n R. Gr a y b il l ................. 481
`
`431
`
`Page 8 of 26
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`517
`
`Ketoconazole Treatment of Coccidioidal Meningitis. By Jo h n R.
`Gr a y b il l , Da v id A. St e v e n s , Jo h n N. Ga l g ia n i, Al a n
`M. Su g a r , Ph il ip C. Cr a v e n , Cl a r k Gr e g g , Mil t o n
`Hu ppe r t , Gr e t c h e n Cl o u d , and Wil l ia m E. Dis mu k e s.... 488
`Azole Derivatives in the Treatment of Paracoccidioidomycosis. By
`Ric a r d o Ne g r o n i....................................................................... 497
`Treatment of Chromoblastomycosis with Itraconazole. By An g e l a
`Re s t r e po , Au r e l io Go n z a l e z, Iv a n Go me z, My r t h a
`Ar a n g o , and Ca t a l in a d e Be d o u t ........................................ 504
`Treatment of Fungal Infections with Semisynthetic Derivatives of
`Amphotericin B. By Pa u l D. Ho e pr ic h , Ne il M. Fl y n n ,
`Mil d r e d M. Ka w a Ch i, Ke n n e t h K. Le e , Ru t h M.
`La w r e n c e , La r r y K. He a t h , and Ca r l P. Sc h a f f n e r .......
`Pathogenesis and Epidemiology of Vulvovaginal Candidiasis. By
`Ja c k D. So b e l .................................................................................. 547
`Prophylactic Use of Clotrimazole in Recurrent Vaginal Candidosis.
`By T. E. C. Bu s h e l l , E. G. V. Ev a n s, P. A. Ll e w e l l y n ,
`J. D. Me a d e n , j. D. Mil n e, and D. W. Wa r n o c k ................. 558
`Single-Dose Oral Fluconazole in the Treatment of Vaginal
`Candidosis. By Ke it h W. Br a mme r and Jo s e ph M. Fe c z k o 561
`Fluconazole for the Treatment of Fungal Diseases in
`Immunosuppressed Patients. By B. Du po n t and E. Dr o u h e t 564
`Parenteral 5-Fluorocytosine in the Therapy of Systemic Mycoses.
`By Fr a n c is A. Min a , Sc o t t J. Ho pk in s , and Bo n n ie
`Ric h e l o ......................................................................................... 571
`Serodiagnosis of Invasive Candidiasis. By Lo w e l l S. Yo u n g and
`Pa u l R. St e v e n s ........................................................................ 575
`New Oral Treatments for Dermatophytosis. By Ro d e r ic k J. Ha y ..
`580
`Topical Treatment of Onychomycosis Using Bifonazole 1% Urea/
`40% Paste. By D. T. Ro b e r t s, R. J. Ha y , V. R. Do h e r t y ,
`M. D. Ric h a r d s o n , and Y. M. Cl a y t o n ................................. 586
`Correlations between Two-Feet-One-Hand Dermatophytosis, Palmar
`Sweating, and Handedness. By S. Be n d e r , M. Wil s o n , and
`Y. Ly n f ie l d ..................................................................................... 588
`
`Part VII. Drug Delivery Systems of Antifungal Drugs
`Liposomes as Carriers for Antifungal Drugs. By Ga b r ie l Lo pe z -
`Be r e s t e in ..................................................................................... 590
`Amphotericin B Encapsulated in Liposomes Administered to
`Cancer Patients. By F. Me u n ie r , J. P. Sc u l ie r , A. Co u n e ,
`
`Page 9 of 26
`
`

`

`C. Br a s s in n e, C. He y ma n , C. La d u r o n , N. Co l l e t t e ,
`C. Ho l l a e r t , D. Br o n , and J. Kl a s t e r s k y ............................. 598
`Index of Contributors.............................................................................. 611
`
`Financial assistance was received from:
`• American Cyanamid Company (Lederle Laboratories)
`• Bausch and Lomb, Inc.
`• Bayer AG
`• Bristol-Myers Company/Pharmaceutical Research and Development
`Division
`• Burroughs Wellcome Co.
`• Eastman Kodak Company/Pharmaceuticals Division
`• Hoechst-Roussel Pharmaceuticals, Inc., USA
`• Imperial Chemical Industries PLC/Pharmaceuticals Division
`• Janssen Pharmaceutica
`• Lilly Research Laboratories/A Division of Eli Lilly and Company
`• Merck, Sharp & Dohme Research Laboratories
`• National Institute of Allergy and Infectious Diseases—National Institutes of
`Health
`• Penn wait Corporation/Pharmaceutical Division
`• Pfizer Central Research, UK
`• Pharma Forschung, Hoechst AG
`• Roerig/A Division of Pfizer Pharmaceuticals
`• Schering Corporation
`•'Shionogi Research Laboratories/Shionogi & Co., Ltd.
`• SmithKline Beckman Corporation
`• E. R. Squibb & Sons
`• Verkauf Pharma/ZPM/Hoechst AG
`
`The New York Academy of Sciences believes it has a responsibility to provide an open forum for
`discussion of scientific questions. The positions taken by the authors of the papers that make up this
`Annal are their own and not necessarily those of the Academy. The Academy has no intent to influence
`legislation by providing such forums.
`
`Page 10 of 26
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`

`

`Fungal Infections and the Search for
`Novel Antifungal Agents
`
`Opening Remarks
`
`VASSIL ST. GEORGIEV
`
`Department of Organic Chemistry
`Pharmaceutical Division
`Pennwalt Corporation
`Rochester, New York 14623
`
`The papers in this volume were presented at the First International Conference on
`Drug Research in Immunologic and Infectious Diseases. The conference, which was
`the first in a projected series of conferences organized under the auspices of the New
`York Academy of Sciences, was dedicated to various topics of drug research in the
`areas of immunologic and infectious diseases. The topics discussed included the latest
`developments in the design, synthesis, and preclinical and clinical evaluation of an-
`tifungal drugs.
`During the last decade or so, the incidence of fungal infections has increased
`dramatically. Deep-seated mycoses are beginning to create serious problems for cli-
`nicians working with certain populations of patients, which include patients that have
`cancer or are immunocompromised or physiologically compromised. For example,
`the disseminated candidiasis is rapidly becoming a major threat to cancer patients,
`especially those with hematologic malignancies.' Such infections occur after intensive
`chemotherapy, thermotherapy, or bone marrow transplants. Recent data have indi-
`cated that over a 4-year period, 11.9% of patients with acute leukemia suffered from
`fungal infections caused by Candida sp. and Torulopsis glabrataf The systemic can-
`didiasis could be often fatal, particularly in neutropenic patients.' Moreover, the
`application of broad-spectrum cephalosporin antibiotics with biliary excretion may
`aggravate the problem even further.
`Another fungal infection that has been coming to light lately is the acute pseu-
`domembranous candidiasis (commonly known as thrush). At present, it is considered
`the most widespread form of oral candidiasis—as many as 5% of all newborn infants,
`5% of cancer patients, and 10% of all hospitalized and debilitated elderly patients
`will come down with the disease.^’
`Among other fungal infections, coccidioidomycosis is emerging as a significant
`threat to the general population.* Soil infection with Coccidioides immitis is the prime
`cause for the disease, which is endemic for the Southwestern United States and for
`Central and South America, and which generally occurs in areas representing some
`of the fastest growing population regions in the world. Increased travel to such regions
`presents yet another threat for further spreading of the disease.
`With the ever-increasing application of immunosuppressive therapy, the role of
`host factors (the T-lymphocyte system) in the defense against fungal infections (es-
`1
`
`Page 11 of 26
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`

`PART V. PHARMACOKINETICS OF ANTIFUNGAL AGENTS
`Pharmacokinetics of Antimycotics
`with Emphasis on Local Treatment
`
`ULRICH TAUBER"
`
`Department of Pharmacokinetics A
`Schering AG
`Berlin, Federal Republic of Germany
`
`INTRODUCTION
`
`Antimycotics in current therapeutic use or in clinical development belong to the
`chemical classes listed in Ta b l e 1.
`The liveliest developments have been going on in the group of azoles. Approxi-
`mately 10 azoles are already on the market, and at least the same number are in the
`clinical trial stage. In recent years, the allylamines with their extremely high efficacy
`against dermatophytes have attracted considerable interest.
`The antimycotics can be classified according to their route of administration and
`their therapeutic use as substances for systemic and local treatment. Substances for
`systemic treatment can be subdivided into those suited for treatment of systemic
`mycoses (such as amphotericin B and flucytosine), those suited for treatment of skin
`mycoses (such as griseofulvin and terbinafin), those suited for treatment of both
`systemic and superficial mycoses (such as ketoconazole), and those showing promise
`for the future (such as itraconazole and fluconazole).
`Substances for local treatment can be discriminated into those for treatment of
`superficial mycoses of the skin and vagina and those for treatment of mycoses of the
`gastrointestinal tract. Substances that are used systemically (intravenously or orally)
`are often also active after local application, but the converse is not necessarily true.
`The potential usefulness of an antimycotic for systemic and/or local application
`is not only determined by its antifungal activity (that is, its intensity and spectrum
`of action), but by its systemic and local tolerance and, last but not least, by its
`pharmacokinetic properties. A prerequisite for a satisfactory therapeutic success is a
`high “bioavailability” of the antimycotic drug at the site where the fungus resides.
`Local concentrations at this site above the minimum inhibitory concentration (MIC)
`or better minimum biocidal concentration (MBC) values must be achieved and main-
`tained over a sufficiently long period of time.
`In the case of systemic therapy, high systemic availability is a prerequisite if one
`is to also obtain high tissue availability at target sites such as the cerebrospinal fluid,
`brain, lungs, kidney, skin, and vagina. To the contrary, when target sites are accessible
`to topical treatment, a high local availability and negligible systemic availability are
`aimed at.
`
`"Address for correspondence: Department of Pharmacokinetics A, Schering AG, Postfach 65
`03 11, D-1000 Berlin 65, Federal Republic of Germany.
`414
`
`Page 12 of 26
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`

`TAUBER: PHARMACOKINETICS OF ANTIMYCOTICS
`
`415
`
`To ensure patient compliance, the dose regimen should be as convenient, simple,
`and short as possible. Because it is the newer therapies that take this into account,
`only the newer orally and topically active substances will be referred to in the following.
`
`PHARMACOKINETICS OF SYSTEMIC ANTIMYCOTICS
`
`Bioavailability at the target site after systemic administration depends on the rate
`and extent of absorption, protein binding, distribution, biotransformation, and excre-
`
`Only the rate and extent of absorption can be influenced by the pharmaceutical
`formulation (micronization, rate of release), whereas other parameters are intrinsic
`characteristics of the drug itself. In Ta b l e 2, brief pharmacokinetic profiles of orally
`administered antimycotics are presented.
`The newer drugs are characterized by higher and more reliable absorption; absence
`of first-pass metabolization; lower protein binding; favorable distribution into the
`cerebrospinal fluid, into the peritoneal fluid, and into the other target compartments;
`and a longer plasma half-life.
`Renal excretion of nearly the whole dose as unchanged substance may be an
`advantage in mycological infections of the urinary tract but needs dose adaptation in
`patients with impaired renal function. If the dose is mainly eliminated by biotrans-
`formation (as in the case of ketoconazole, itraconazole, and terbinafine), a dose
`reduction in patients with impaired kidney or liver function does not seem to be
`necessary. But a possible induction or inhibition of P-450 enzymes-and thus also an
`interaction at the site of biotransformation with other drugs—has to be excluded.
`
`PHARMACOKINETICS OF TOPICAL ANTIMYCOTICS
`
`Drugs for Treatment of Mycoses of the Gastrointestinal Tract
`
`For treatment of intestinal candidoses and for elimination of fungi as sources of
`reinfection of the skin and vagina, the antimycotic must be bioavailable in dissolved
`form within the intestinal lumen. Any absorption through the mucosa would decrease
`the local bioavailability of the drug in the lumen and lead to an undesirable systemic
`loading.
`■ . n
`The orally nonabsorbable polyene macrolide antimycotics amphotericin B, nystatin,
`and natamycin have been successfully used for these purposes for a long period of
`time. Orally administered imidazoles are not suitable because they are absorbed, and
`sufficiently high concentrations cannot be maintained in the intestinal lumen, especially
`in the terminal segments.
`
`Page 13 of 26
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`416
`
`ANNALS NEW YORK ACADEMY OF SCIENCES
`
`Drugs for Treatment of Superficial Mycoses of the Skin
`
`Former treatment with unspecifically acting antiseptics has been thoroughly re-
`placed by treatment with specifically acting substances. Antimycotics of all the chem-
`ical classes shown in Ta b l e 1 are used for topical treatment. Whereas systemic
`administration needs specific pha