Chemotherapy of Fungal Diseases

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.