Chemotherapy of Fungal Diseases

ISBN-13: 9783642754609 / Angielski / Miękka / 2011 / 558 str.

D. Armstrong;F.T. Boyle;M. Debono

Opis

Fungal diseases have been with us from antiquity; interest in the chemo- therapy of fungal disease has exploded in the past decade. To plan and pro- duce a book on the topic of antifungal chemotherapy has come as a personal challenge - and something of an eye-opener - towards the end of my re- search career. A landmark publication which still merits reading is Antifungal Chemotherapy (John Wiley & Sons, Chichester, UK), edited by David Speller, which appeared in 1980. However, the fact that ketoconazole, the first of the modern, orally active, wide-spectrum antifungals, attracted no more than two sentences in it indicates just how far we have come in the 1980s. A steady stream of original papers and a number of conference proceedings have chronicled this progress in drug research; outstanding among the latter are the proceedings of an international telesymposium, entitled Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents, edited by Robert Fromtling (J.R. Prous, Barcelona, 1987) and volume 544 of the Annals of the New York Academy of Sciences, entitled Antifungal Drugs, edited by Vassil St. Georgiev, and containing papers and posters presented at a most enjoyable 3-day conference held at Garden City, New York, in the autumn of 1987.

Spis treści

Section I. Drug Discovery.- 1 Drug Discovery: A Chemist’s Approach.- A. Introduction.- B. Development of a Lead.- C. Identification of a Lead.- I. Fungal Sterol Metabolism — A Target for Lead Identification.- II. ?24 - Transmethylation in Yeast and Fungal Sterol Synthesis.- III. Regulation of A24 ~ Transmethylation.- IV. In House Lead Structure Selection and Biological Investigations.- D. Concluding Remarks.- References.- 2 Drug Discovery: A Biochemist’s Approach.- A. Introduction.- B. Factors Affecting the Choice of Target.- I. The Cell Wall as a Barrier to Drug Uptake.- C. Potential Targets.- I. External to the Plasma Membrane.- 1. Structural Polysaccharides.- 2. Cell Wall Associated Enzymes.- 3. Plasma Membrane Associated Targets.- II. Internal Targets.- 1. Transport of Drugs into Sensitive Fungi.- 2. Plasma Membrane Proteins.- 3. Pathways of Intermediary Metabolism.- 4. Macromolecular Synthesis.- III. Miscellaneous Targets.- 1. Drugs Preventing Adhesion.- 2. Dimorphism.- 3. The Cytoskeleton.- 4. Exocellular Compounds Involved in Disease.- IV. Which Target?.- D. Short-Term Solutions to Antifungal Therapy.- I. Combination Therapy.- II. Drug Formulation.- E. Long-Terms Developments.- References.- 3 Drug Discovery: Nature’s Approach.- A. Introduction.- B. Sources of Samples for Screening.- I. Soil.- II. Marine Organisms.- C. The Fungal Cell Wall as an Antifungal Target.- I. Biomolecular Composition and Approaches to Screening for Inhibition of Cell Wall Biosynthesis.- II. Inhibition of ?-(1,3)-Glucan Synthesis.- III. Inhibitors of Chitin Synthase.- D. Biological Evaluation of Antifungal Agents.- E. Conclusion.- References.- 4 Screening and Evaluation In Vitro.- A. Purpose of Screening.- B. Methods of Screening.- C. Choice of Organisms and Conditions.- D. Choice of Media.- E. A Workable In Vitro Screen.- F. Interpretation of Screen Results.- G. Relevance of Screen.- H. Evaluation In Vitro.- J. Features of Activity.- K. Conclusions.- References.- 5 Screening And Evaluation In Vivo.- A. Preliminary Considerations.- B. Types of Screen.- C. The Multi-Infection Screen.- D. Further Evaluation.- I. Candidosis.- 1. Rat Vaginitis.- 2. Intestinal Infections.- 3. Systemic Infections.- 4. Skin Infections.- 5. Other Infections.- II. Dermatophytosis.- III. Cryptococcosis.- IV. Aspergillosis.- V. Other Mycoses.- 1. Coccidioidomycosis.- 2. Paracoccidioidomycosis.- 3. Histoplasmosis.- 4. Blastomycosis.- 5. Sporotrichosis.- 6. Miscellaneous Mycoses.- E. Extrapolation to Clinical Use.- References.- Section II. Drug Development.- 6 Mode Of Action Studies.- A. Introduction.- B. Target: Nucleic Acid Synthesis and Cell Division.- I. 5-Fluorocytosine.- II. Griseofulvin.- C. Target: Cell Membrane.- I. Polyene Macrolides.- II. Ergosterol Biosynthesis Inhibitors.- 1. Imidazole and Triazole Derivatives.- 2. Morpholine Derivatives.- 3. Allylamines.- 4. Thiocarbamate Antifungals.- 5. Conclusions.- D. Target: Cell Wall Synthesis.- I. Chitin Synthase Inhibition.- II. Glucan Synthesis.- References.- 7 Pharmacokinetic Aspects of Antifungal Therapy.- A. Introduction.- B. Pharmacokinetic and Metabolic Concepts.- I. In Vitro Potency Versus In Vivo Efficacy.- II. Analysis of Samples.- III. Assessment of Absorption and Systemic Availability.- IV. Distribution Parameters.- V. Assessment of Duration of Action.- VI. Summary.- C. Pharmacokinetics of Clinically Used Antifungal Agents.- I. Non-Azoles.- 1. Amphotericin B.- 2. 5-Fluorocytosine.- II. First Generation Imidazole Drugs.- III. Ketoconazole.- IV. Novel Triazole Agents.- D. Conclusions.- References.- 8 Hepatic and Endocrine Effects of Azole Antifungal Agents.- A. Introduction.- B. Nature of Cytochrome P-450.- C. Mode of Interaction of Azoles with Cytochrome P-450.- D. Effects of Azoles on Mammalian Hepatic Cytochromes P-450.- I. In Vitro Metabolism Studies.- II. In Vivo Drug Interaction Studies.- III. Induction of Cytochromes P-450.- E. Endocrine Effects of Azoles.- I. Mammalian Endocrine System.- II. Effects of Ketoconazole on Steroidogenic Tissues.- III. Other Endocrine Effects of Ketoconazole.- IV. Effect of Other Imidazole Antifungal Agents on Steroidogenesis.- V. New Antifungal Agents.- VI. Clinical Use of Ketoconazole in Endocrinology.- 1. Use in Cortisol Overproduction.- 2. Use in Androgen Overproduction.- 3. Other Clinical Uses.- VII. Assessment of Anti-Steroidogenic Biopotency and Site of Action of Antifungal Agents.- F. Conclusions.- References.- 9 Structure-Teratogenicity Relationships Among Antifungal Triazoles.- A. Introduction.- B. Materials and Methods.- C. Results.- I. In Vitro Assays.- II. In Vivo Teratogenicity.- 1. Monotriazole Tertiary Alcohols.- 2. Bistriazole Tertiary Alcohols.- D. Discussion.- I. Monotriazole Tertiary Alcohols.- II. Bistriazole Tertiary Alcohols.- III. Correlation Between IC50T and In Vivo Teratogenicity.- 1. Monotriazole Tertiary Alcohols.- 2. Bistriazole Tertiary Alcohols.- E. Conclusions.- References.- 10 Formulation.- A. Introduction.- B. Topical Formulations.- I. Skin Infections.- 1. Penetration Studies.- 2. Therapeutic Studies.- 3. Pharmacokinetic Studies.- II. Nail Infections.- 1. In Vitro Models.- III. Vaginal Infections.- 1. Absorption Studies.- 2. Therapeutic Studies.- C. Oral Formulations.- D. Parenteral Formulations.- References.- 11 Regulatory Procedures.- A. Introduction.- B. A Short History and Some of the Landmarks in Drug Development and Regulation.- I. Early Days.- II. The Development of the Pharmacopoeias.- III. The Rise of the Pharmaceutical Industry.- IV. Self-Medication, Patent Medicines and Secret Remedies.- V. Poisons and Dangerous Drugs.- VI. The Therapeutic Substances Act.- VII. Thalidomide and After.- VIII. Evolution of Regulatory Procedures in the USA.- IX. Summary.- C. Who Is Involved? The Regulators and the Regulated.- D. Data Requirements for a New Drug.- E. The Regulatory Process: Pre-Submission.- I. The Activities and the Time Scale.- II. The Cost.- III. The Scale of the Marketing Application.- IV. Compiling the Marketing Application.- V. Structuring the Marketing Application.- VI. Expert Reports.- VII. ‘Second Wave’ Countries.- F. The Regulatory Process: Post-Submission.- I. Processing of a Marketing Application Within the UK Department of Health.- II. The Committee for Proprietary Medicinal Products.- III. The Regulatory Process in ‘Second Wave’ Countries.- G. Regulatory Processes for Marketed and Older Products.- I. Supplementary Applications.- II. Drug Review Programmes.- III. Maintaining the Consistency of Prescribing Information.- H. Discussion.- References.- 12 Clinical Trials.- A. Introduction.- B. Why Clinical Trials Exist.- C. General Principles in the Study of Antifungal Drugs.- I. Evaluation of Drug Efficacy in Epidermal and Mucosal Mycotic Infections.- 1. What is the Meaning of the Mycological Test?.- 2. How Can Signs and Symptoms Best be Evaluated?.- 3. What is the Significance of and Best Way to Evaluate Relapse or Reinfection?.- II. Evaluation of Drug Efficacy in Systemic Mycoses.- III. Documentation of Drug Tolerability During Topical Application.- IV. Documentation of Drug Tolerability During Oral or Intravenous Drug Use.- D. Organization of Clinical Trials for the Treatment of Dermatomycoses.- I. Tolerability and Pharmacokinetic Assessment in Healthy Volunteers (Phase I).- II. Open-Label Efficacy Trials (Phase I).- III. Dose Finding and Duration Finding Studies (Phase II).- IV. Exploring Drug Efficacy and Tolerability in Various Diseases (Phase III).- V. Evaluation of Special Features of the Drug; Profiling Studies (Phase IV).- E. Special Aspects of Clinical Trials in the Treatment of Systemic Mycoses.- F. Statistical Issues in the Conduct of Clinical Trials.- G. Selected Issues in Protocol and Investigator Brochure Preparation, Good Clinical Practice Implementation, and Final Study Report Documentation.- I. Protocol and Investigator Brochure Preparation.- II. Good Clinical Practice Implementation.- III. Final Study Report Documentation.- H. Summary and Conclusions.- References.- Section III. Clinical Usage.- 13 Clinical Usage — A Dermatologist’s Viewpoint.- A. Introduction.- B. The Superficial Mycoses.- I. Dermatophyte Infection.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- II. Superficial and Mucocutaneous Candidosis.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- III. Pityriasis Versicolor.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- IV. Less Common Superficial Fungal Infections of Nails.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- V. Less Common Superficial Fungal Infections of Skin and Hair.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- VI. Otomycosis.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- C. The Subcutaneous Mycoses.- I. Mycetoma.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- II. Chromomycosis.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- III. Sporotrichosis.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- IV. Phaeohyphomycosis.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- V. Lobomycosis.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- VI. Zygomycosis (Phycornycosis).- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- VII. Rhinosporidiosis.- 1. Aetiology and Epidemiology.- 2. Clinical Features.- 3. Differential Diagnosis.- 4. Laboratory Diagnosis.- 5. Treatment.- D. Present Therapeutic Practice and Future Needs.- I. Introduction.- II. Choice of Preparation.- 1. Introduction.- 2. The Superficial Mycoses.- 3. The Subcutaneous Mycoses.- III. Factors Influencing Treatment Failure.- 1. Lack of Compliance.- 2. Host Factors.- 3. Fungal Pathogenicity.- 4. Drug Factors.- 5. Inadequate Treatment.- 6. Epidemiological Factors.- IV. Future Requirements.- References.- 14 Therapeutic Considerations in Fungal Vaginitis.- A. Introduction.- B. Therapeutic Principles.- I. Topical Agents for Acute Candida Vaginitis.- 1. Polyenes.- 2. Azoles.- II. Status of Short Course Topical Therapy.- III. Oral Systemic Agents for Candida Vaginitis.- C. Chronic and Recurrent Vulvovaginal Candidosis.- I. Pathogenesis of Recurrent Vulvovaginal Candidosis.- II. Treatment of Recurrent and Chronic Candida Vaginitis.- III. Resistance to Antimycotic Agents.- D. Acute Vaginitis in Pregnancy.- E. Management of Sexual Partners of Women with Vulvovaginal Candidosis.- F. Therapeutic Caveats in Vulvovaginal Candidosis.- G. Summary.- References.- 15 An Infectious Disease Specialist’s Viewpoint.- A. Introduction.- B. The Problem.- C. Diagnosis.- D. Therapy.- E. Prospect for Vaccines.- F. The Future.- References.- 16 Management of Fungal Infections in Patients with Neoplastic Diseases.- A. Introduction.- B. Principles of Host Defense in Patients with Neoplastic Diseases.- C. Definitions and Classification of Nosocomial Fungal Infections.- I. Aspergillosis.- 1. Microbiology.- 2. Hospital Epidemiology.- 3. Clinical Manifestations.- 4. Treatment.- II. Zygomycosis.- 1. Microbiology.- 2. Hospital Epidemiology.- 3. Clinical Manifestations.- 4. Treatment.- III. Other Type I (Hospital-Acquired) Nosocomial Fungal Infections in Cancer Patients.- 1. Pseudallescherosis.- 2. Fusariosis.- 3. Phaeohyphomycosis.- IV. Candidosis.- 1. Microbiology.- 2. Hospital Epidemiology.- 3. Clinical Manifestations.- 4. Treatment.- V. Trichosporonosis.- VI. Malassezia furfur Fungemia.- VII. Reactivation of Latent Fungal Infections.- VIII. Fungal Infections in Patients with Combined Neoplastic Diseases and AIDS.- D. Future Directions.- References.- 17 Fungal Infections and AIDS.- A. Introduction.- B. Candidosis.- C. Cryptococcosis.- D. Histoplasmosis.- E. Coccidioidomycosis.- F. Dermatophytes.- G. Seborrhoeic Dermatitis.- H. Other Mycoses.- References.- 18 Older Drugs.- A. Introduction.- B. Amphotericin B.- I. History.- II. Mode of Action.- III. Resistance.- IV. Pharmacokinetics.- V. Indications.- VI. Administration.- VII. Toxicity.- C. 5-Fluorocytosine.- I. History.- II. Mode of Action.- III. Resistance.- IV. Pharmacokinetics.- V. Indications.- VI. Administration.- VII. Toxicity.- References.- 19 Systemic Azole Antifungal Drugs — Into the 1990s.- A. The Evolution of Azole Antifungals in Clinical Use.- I. Introduction: Why Not Stay with ‘Good Old’ Amphotericin B?.- II. The Dawn of the Era of Azole Antifungals.- 1. The First Efforts ’Fail’ — Clotrimazole.- 2. The Potential Is Demonstrated — Miconazole.- III. The Dam Breaks with Ketoconazole.- IV. The ‘Second Generation’ Azoles.- 1. Itraconazole — Broad Spectrum with Less Toxicity.- 2. Fluconazole — Targeting a Disease Based on Preclinical Studies.- 3. SCH39304 — Potent ‘New Kid on the Block’.- V. Further out on the Horizon.- 1. BAYER 3783.- 2. Saperconazole — Son of Itraconazole.- VI. A Drug that was Retired Before Its Time — ICI 153,066.- B. Interrelation of the Azoles.- C. Patterns of Use of the Antifungal Azoles in the 1990s.- I. Use in Neutropenic Patients.- 1. Treatment of Established Candidosis and Aspergillosis.- 2. Empiric Antifungal Therapy for Candidosis and Aspergillosis.- 3. Prophylaxis of Candidosis and Aspergillosis.- II. Use in Fungal Infections in Other Immunocompromised States.- 1. AIDS.- 2. Cryptococcosis.- III. Use in Nonimmunocompromised Patients.- 1. Major Endemic Mycoses.- 2. Miscellaneous Mycoses.- D. Summary.- References.- 20 Terbinafine.- A. Introduction.- B. Chemistry and Mode of Action.- I. Chemistry.- II. Mode of Action.- III. Measurement of Terbinafine in Plasma, Body Fluids and Tissue.- C. Antifungal Activity.- I. Fungicidal and Fungistatic Actions.- II. Morphological Effects of Terbinafine on Fungi.- III. Spectrum of Antifungal Activity.- D. Activity in Animals.- I. Metabolism.- II. Antifungal Activity.- E. Toxicology.- I. Acute and Chronic Toxicity.- II. Fertility, Reproduction, Teratogenicity and Mutagenicity.- F. Clinical Results; Efficacy and Tolerability.- I. Pharmacokinetics in Humans.- II. Efficacy of Terbinafine.- III. Tolerability of Oral and Topical Terbinafine.- G. Summary.- References.- 21 Amorolfine.- A. Introduction.- B. Preclinical Results.- I. Antifungal Activity of Amorolfine In Vitro.- 1. Fungistatic Activity.- 2. Fungicidal Activity.- II. Therapeutic Efficacy in Animal Models.- 1. Deep Mycoses.- 2. Topical Mycoses.- C. Clinical Studies.- I. Human Pharmacokinetics.- 1. Dermal Penetration.- 2. Vaginal Absorption.- II. Human Pharmacology.- 1. Persistence in the Skin.- 2. Dermal Tolerance.- 3. Persistence Under the Nail.- 4. Vaginal Tolerance.- III. Therapeutic Trials.- 1. Dermatomycosis.- 2. Onychomycoses.- 3. Vulvovaginal Mycosis.- IV. Conclusion.- References.- Section IV. Where Next?.- 22 Other Compounds in Development.- A. Cilofungin.- I. Antifungal Activity In Vitro.- II. Antifungal Activity In Vivo.- III. Mode of Action.- IV. Toxicology.- V. Pharmacokinetics.- VI. Current Status.- B. SCH 39304 (SM 8668).- I. Antifungal Activity In Vitro.- II. Antifungal Activity In Vivo.- III. Pharmacokinetic Studies in Animals.- IV. Current Status.- C. ICI 195,739.- I. Antifungal Activity In Vitro.- II. Antifungal Activity In Vivo.- III. Mode of Action Studies.- IV. Pharmacokinetics and Toxicology.- D. Other Azoles.- I. Saperconazole.- II. SDZ 89-485.- III. BAY R 3783 (Electrazole).- E. Non-Azoles.- I. SDZ 87-469.- II. BMY 28567 (Pradimycin).- III. Nikkomycin Z.- References.