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Pharmacology of the Skin I
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Table of Contents

Section A: Pharmacology of Skin Systems.- 1 The Epidermis.- A. The Structure of Epidermis.- I. The External Surface of Skin.- II. Histology of Epidermis.- 1. Introduction.- 2. The Basement Membrane.- 3. Fine Structure of Epidermal Cells.- 4. Lamellar Granules.- 5. Intercellular Junctions.- 6. Regional Differences in Epidermal Structure.- B. Epidermal Replacement.- I. Epidermal Renewal Rates.- II. Effects of External Influences.- III. Migration Out of the Basal Layer.- IV. The Formation of Epidermal Cell Columns.- V. The "Zipper Mechanism" Leading to Column Formation.- C. The Langerhans Cell.- I. Morphological Features.- II. Origin.- III. Functional Properties.- IV. Role in Disease.- D. Conclusion.- References.- 2 Keratin.- A. Introduction.- B. Fibrous Proteins.- C. Keratohyalin.- D. Cornifled Envelope.- E. Desmosomes.- F. Membrane Coating Granules.- References.- 3 Regulation of Epidermal Growth.- A. Cyclic Nucleotides.- I. Effects of Cyclic AMP on Different Epidermal Cells.- II. Cyclic GMP.- III. Receptors.- B. Prostaglandins.- C. Epidermal Growth Factor.- I. Chemical Composition and Properties.- II. Human EGF.- III. Level of EGF.- IV. EGF Receptor.- V. EGF in Cell Proliferation and Differentiation.- D. Chalones of the Skin.- E. Calcium and Calmodulin.- F. Histamine.- G. Conclusion.- References.- 4 Epidermal Lipogenesis (Essential Fatty Acids and Lipid Inhibitors).- A. Introduction and Historical Considerations.- B. Essential Fatty Acids.- I. Biosynthesis and Metabolism.- II. Physiological Functions in the Skin.- III. Role as Precursors of Prostaglandins and Related Lipids.- C. Essential Fatty Acid Deficiency.- I. Macroscopic and Microscopic Appearance of the Skin During Deficiency.- II. Altered Patterns of Polyunsaturated Fatty Acids.- III. Increased Metabolic Activity During Deficiency.- IV. Deficiency in Human Skin.- D. Epidermal Lipogenesis and Its Regulation.- I. Interrelationships of Metabolic Pathways.- II. Regulation of Epidermal Lipogenesis.- References.- 5 Fibroblasts, Collagen, Elastin, Proteoglycans and Glycoproteins.- A. Introduction.- B. Fibroblasts Are Differentiated Cells.- C. Collagen.- I. Molecular Structure and Distribution.- II. Biosynthesis.- III. Polymerisation.- IV. Degradation.- D. Elastin.- I. The Elastic Fibre.- II. Biosynthesis, Polymerisation and Degradation.- E. Proteoglycans and Glycosaminoglycans.- I. Molecular Structure.- II. Biosynthesis, Organisation and Degradation.- F. Structural Glycoproteins.- I. Fibronectin, Laminin, Entactin and Others.- II. Biosynthesis.- G. Regulation and Diseases.- I. Fibroblasts.- II. Collagen.- III. Elastin.- IV. Proteoglycans.- V. Structural Glycoproteins.- H. Interaction Between the Macromolecules of the Connective Tissue.- J. Conclusions.- References.- 6 Dermal Blood Vessels and Lymphatics.- A. Dermal Blood Circulation.- I. Functions of Dermal Vascular Bed.- II. Anatomy of Dermal Blood Vessels.- 1. Distributing Arteries.- 2. Arterioles and Metarterioles.- 3. Capillary Bed.- 4. Arteriovenous Anastomoses (Shunts).- 5. Venules.- III. Physiology of Dermal Blood Flow.- 1. Role of Cutaneous Circulation in Body Temperature Regulation.- IV. Neural Regulation of Dermal Blood Flow.- 1. Sympathetic Trunks and Postganglionic Pathways.- 2. Adrenergic Sympathetic Control of Dermal Vessels.- 3. Adrenergic Neuroeffector End Organs.- 4. Cutaneous Vasodilator Sympathetic Nerves.- V. Other Mechanisms for Regulation of Dermal Blood Flow.- 1. Hormonal Control.- 2. Local Control.- VI. Therapeutic Modulation of Dermal Blood Flow by Drugs.- 1. Vasodilator Agents.- 2. Vasoconstrictor Agents.- B. Dermal Lymphatic Circulation.- I. Anatomical Considerations.- 1. Dermal Lymph Capillaries (Initial Lymphatics).- 2. Dermal Collecting Lymph Channels and Trunks.- 3. Dermal Lymphatic System in the Limbs.- II. Physiological Considerations.- 1. Methods for Study of Lymph Flow.- 2. Mechanisms Involved in Passage of Fluids and Particulate Matter into Lymphatic Capillaries.- 3. Factors Involved in Transport of Lymph.- 4. Alterations in Concentration of Lymph in Its Passage Through the Lymphatics.- 5. Response of Lymphatics to Inflammation.- III. Pharmacological Considerations.- References.- 7 Blood Flow - Including Microcirculation.- A. Visual Assessment.- B. Thermal Measurements.- I. Thermometry and Thermography.- II. Thermal Clearance (Conductance).- C. Radioisotopic Techniques.- I. Isotope Extraction.- II. Clearance of Locally Injected Radiolabels.- D. Red Blood Cell Velocity Measurements.- E. Doppler Shift Techniques.- I. Ultrasound Doppler.- II. Laser Doppler.- F. Plethysmography.- G. Electromagnetic Flowmeters.- H. Conclusion.- References.- 8 Immunopharmacology of Mast Cells.- A. Mast Cell Content of Human Skin.- B. Mast Cell Structure.- C. The Ontogeny of Mast Cells.- D. Preformed Granule-Associated Mediators.- I. Biogenic Amines.- 1. Histamine.- 2. 5-Hydroxytryptamine.- II. Neutral Proteases.- III. Acid Hydrolases.- IV. Other Mast Cell Enzymes.- V. Chemotactic Factors.- VI. Proteoglycans.- E. Newly Generated Inflammatory Mediators.- I. Cyclo-oxygenase Products of Arachidonic Acid.- II. The Lipoxygenase Pathway.- III. Platelet Activating Factor.- F. Mechanisms of Mast Cell Activation.- I. Mechanisms of IgE-Dependent Mediator Secretion from Mast Cells.- II. Human Mast Cell Activation by IgE-Dependent and IgE-Independent Stimuli.- G. Pharmacological Modulation of Mediator Secretion from Skin Mast Cells.- H. Conclusions.- References.- 9 Lymphocytes.- A. Introduction.- B. Lymphokines.- C. Lymphokines as Mediators of Cellular Immunity.- D. Regulation of Lymphocyte Activation.- I. Role of Arachidonic Acid.- II. Role of Interleukins.- E. Conclusion.- References.- 10 Structure, Function and Control: Afferent Nerve Endings in the Skin.- A. Introduction.- B. Fibre Composition of Cutaneous Nerves.- C. Mechanoreceptors.- I. Introduction.- II. Rapidly Adapting Mechanoreceptors.- 1. Pacinian Corpuscles.- 2. RA and Field Receptors.- 3. Hair Follicle Receptors.- III. Slowly Adapting Mechanoreceptors.- 1. Type SA I.- 2. Type SA II.- 3. Slowly Adapting Hair Follicle Units.- 4. C-Mechanoreceptors.- IV. Summary.- D. Thermoreceptors.- I. Cold Units.- II. Warm Units.- E. Nociceptors.- I. High Threshold Mechanoreceptor Units.- II. Polymodal Nociceptor Units.- F. Overview: Types of Cutaneous Mechanoreceptor, Thermoreceptor and Nociceptor.- G. Modulation of Sensitivity of Cutaneous Receptors by Drugs.- I. Introduction.- II. Catecholamines.- 1. Mechanoreceptors.- 2. Thermoreceptors.- 3. Nociceptors.- 4. Nerve Endings in Neuromas.- III. Inflammatory Mediators.- 1. Histamine.- 2. Serotonin.- 3. Bradykinin.- 4. Prostaglandins.- 5. Mediators and Sensitisation.- IV. Other Agents that Excite Cutaneous Receptors.- 1. Capsaicin.- 2. Substance P.- 3. Acetylcholine.- 4. Other Irritants.- V. Other Agents that Modulate the Responses of Cutaneous Nerve Endings.- VI. Overview: Drugs and Cutaneous Receptors.- References.- 11 Sweat Glands: Eccrine and Apocrine.- A. Anatomical Features.- B. Fine Structure.- I. Eccrine Glands.- II. Apocrine Glands.- C. Innervation.- I. Eccrine Glands.- II. Apocrine Glands.- D. Secretory Function of Eccrine Glands.- I. The Secretory Process and Sweat Formation.- E. Apocrine Gland Function.- F. Pharmacology of Sweating.- I. Eccrine Glands.- II. Neurohumoral Aspects.- 1. Denervation.- 2. Axon Reflex Sweating.- 3. Hyperhidrosis.- III. Apocrine Glands.- References.- 12 Thermoregulation and the Skin.- A. Skin Blood Flow.- I. Vascular Effects on Heat Exchange.- II. Nervous Control of Cutaneous Blood Flow.- III. Reflex Control of Skin Blood Flow.- IV. Central Control of Skin Blood Flow.- V. Interactions Between Thermal Receptors.- VI. Effects of Local Temperature.- B. Sweating.- I. Neural, Humoral and Local Control.- II. Acclimation and Fatigue of Sweat Glands.- References.- 13 Hair and Nail.- A. Hair Follicle and Hair Shaft.- I. Follicle Structure.- II. Hair Shaft Structure.- III. Hair Cycle.- IV. Endocrine Control Factors.- B. Nail Apparatus.- References.- 14 The Sebaceous Glands.- A. Introduction.- B. Development.- C. Sebum.- I. Formation.- II. Composition.- III. Function.- IV. Factors Affecting the Rate of Sebum Production.- D. Control.- I. Non-endocrine Control.- II. Endocrine Control.- 1. Androgens.- 2. Oestrogens.- 3. Progesterone.- 4. Glucocorticoids.- 5. Thyroid Hormones.- 6. Insulin.- 7. The Pituitary.- 8. The Early Endocrine Environment.- References.- 15 Metabolism of Sex Steroids.- A. Introduction.- B. Hydroxysteroid Dehydrogenase Activities.- I. Androgens.- 1. Dehydroepiandrosterone.- 2. ?4-Androstene-3,17-dione.- II. Oestrogens.- III. Progesterone.- C. 5?-Reduction of Testosterone and Progesterone.- I. Testosterone.- II. Progesterone.- D. 3?- and 3?-Hydroxysteroid Dehydrogenases.- I. Androgens.- II. Progesterone.- E. Normal Control of Androgen Metabolism in Human Skin.- F. Abnormal Control of Androgen Metabolism in Human Skin.- G. Conclusion.- References.- 16 Melanophores, Melanocytes and Melanin: Endocrinology and Pharmacology.- A. Pigment Cells.- B. Dermal Melanophores.- C. Epidermal Melanophores.- D. Melanosome Dispersion.- E. Melanogenesis.- F. Melanocyte Stimulating Hormone.- I. Physiological Significance of MSH Peptides as a Pigmentary Hormone in Man.- G. Catecholamines.- H. Melatonin.- J. Steroids.- K. Prostaglandins.- References.- 17 Cytokines in Relation to Inflammatory Skin Disease.- A. Introduction.- B. Interleukins: Structure and Physicochemical Properties.- C. Biological Activities of Interleukins.- D. Interleukins and Normal Skin.- E. Dermatological Disorders and IL-1.- F. Dermatological Disorders and IL-2.- G. Dermatological Disorders, Interleukins, and Leukocyte-Endothelial Interactions.- H. Comment.- References.- Section B: Autocoids in Normal and Inflamed Skin.- 18 Histamine, Histamine Antagonists and Cromones.- A. Introduction.- B. Histamine Content of Skin.- C. Histamine-Forming Capacity in Skin.- D. Histamine Catabolism in Skin.- E. The Release of Histamine from Skin.- F. Application of Histamine to the Skin and the Pharmacological Modification of Its Effects.- I. Vascular Effects.- II. Sensory Effects.- III. Other Effects.- IV. Anti-allergic Drugs.- G. Clinical Conditions Associated with Histamine in Skin.- H. Concluding Remarks.- References.- 19 Kallikreins and Kinins.- A. Introduction.- B. Chemistry and Biological Activities of Kinins.- I. Principal Types of Kinins.- II. Mechanisms of Biological Actions.- III. Actions on Blood Vessels.- IV. Pain-Producing Effects.- V. Other Actions of Kinins.- C. Kinin Formation in Mammals.- I. Specific and Non-specific Kinin-Forming Enzymes.- II. Kinin Formation by Plasma Kallikreins and Other Plasma Enzymes.- III. Kinin Formation by Blood Cells.- IV. Glandular Kallikreins.- V. Kinin Formation in Human Skin.- D. Inhibitors of Kinin Formation.- E. Fate in the Body of Formed Plasma Kinins.- F. Kinins in Experimental and Clinical Damage of Human Skin.- I. Assessment of the Role of Kinins.- II. Inflammation and Related Conditions.- G. Concluding Remarks.- References.- 20 Acetylcholine, Atropine and Related Cholinergics and Anticholinergics.- A. Cholinergic Agents.- I. Acetylcholine.- 1. Distribution.- 2. Biosynthesis and Storage.- 3. Physiological Inactivation.- 4. Acetylcholine in Skin.- 5. Pharmacological Actions.- 6. Functional Significance in Skin.- II. Anticholinesterase Agents.- 1. Pharmacological Actions.- III. Other Cholinomimetic Agents.- 1. Stable Esters of Choline.- 2. Pilocarpine.- B. Anticholinergic Drugs.- I. Chemistry.- 1. Belladonna Alkaloids and Their Derivatives.- 2. Synthetic Anticholinergic Agents.- II. Mechanism of Action.- III. Pharmacological Actions.- 1. Cardiovascular System.- 2. Gastrointestinal Tract.- 3. Respiratory Tract.- 4. Eye.- 5. Urinary Tract.- 6. Secretory Glands.- 7. Central Nervous System.- 8. Skin.- IV. Adverse Effects.- V. Other Classes of Drug Possessing Pronounced Anticholinergic Activity.- 1. Histamine H1-Receptor Antagonists.- 2. Tricyclic Antidepressants.- 3. Haloalkylamine ?-Adrenoceptor Blocking Agents.- References.- 21 Prostaglandins, Leukotrienes, Related Compounds and Their Inhibitors.- A. Discovery of the Prostaglandins.- B. Biosynthesis of Prostaglandins.- C. Action of Prostaglandins in Skin.- I. Vasodilatation.- II. Oedema Formation.- III. Leukocyte Accumulation.- IV. Pain.- D. Generation of Prostaglandins in Skin.- E. Discovery of the Lipoxygenase Pathway.- F. The Leukotrienes.- G. Action of Lipoxygenase Products in Skin.- I. Vasoactive Effects.- II. Leukocyte Accumulation.- III. Oedema Formation.- H. Generation of Lipoxygenase Products in Skin.- J. Inhibitors of Arachidonate Metabolism.- K. Conclusion.- References.- 22 Slow Reacting Substance of Anaphylaxis.- A. Introduction.- B. Physico-chemical Characterisation.- C. Functional Characterisation.- D. Inactivation of SRS-A.- E. Summary.- References.- 23 Complement.- A. Introduction.- B. The Classical Pathway.- C. The Alternative Pathway.- D. Terminal Events in the Complement Cascade.- E. Biological Activities Resulting from Complement Activation.- I. Diffusible Products.- II. Retained Complement Products.- III. Membrane Lysis.- IV. Solubilisation of Immune Complexes.- F. Regulation of Complement Activation.- I. CT Inhibitor.- II. C4 Binding Protein.- III. Factors H and I.- G. Inherited Deficiencies of Complement Components.- I. Bacterial Infections.- II. Auto-immune or Immune Complex Diseases.- H. Complement in Skin Disease.- I. Immune Complex Disease.- II. Bullous Skin Diseases.- References.- 24 Neutrophil and Eosinophil Chemotaxis and Cutaneous Inflammatory Reactions.- A. Introduction.- B. Methods of Measuring Chemotaxis and Cell Accumulation.- C. Chemotactic Factors for Neutrophils and Eosinophils.- I. Complement-Derived Factors.- II. Cell-Derived Factors.- III. Lymphokines.- IV. Coagulation Products.- V. Micro-organisms.- D. Other Properties of Chemotactic Factors.- E. Control of Neutrophil and Eosinophil Locomotion.- F. Defects in Chemotaxis.- I. Impaired Generation of Chemoattractants.- II. Inhibition of Chemotaxis.- III. Intrinsic Disorders of Granulocyte Locomotion.- G. Skin Diseases Associated with Neutrophil Infiltration.- H. Skin Disease Associated with Eosinophil Infiltration.- J. Conclusions.- References.- 25 Neuropeptides and the Skin.- A. Introduction.- B. Biochemistry of Peptide-Mediated Signalling.- C. Distribution and Functions of Peptides in Mammalian Skin.- I. Tachykinins and CGRP.- II. Vasoactive Intestinal Peptide.- III. Other Neuropeptides.- IV. Neuropeptides as Growth Factors?.- D. Conclusions and Clinical Implications.- References.- 26 Polyamines.- A. Occurrence and Metabolism of Polyamines.- I. Introduction.- II. Structure and Occurrence.- III. Polyamine Metabolism.- IV. Regulation of Polyamine Biosynthesis.- V. Inhibitors of Polyamine Biosynthesis.- B. Polyamines and Growth.- I. Polyamines and Cell Growth.- II. Polyamines and Tissue Growth.- III. The Biochemical Role of Polyamines.- C. Polyamines and Hyperproliferative Diseases.- D. Polyamines in Skin.- I. Induction of Polyamine Biosynthesis in Skin.- 1. Wound Healing.- 2. Epidermal Growth Factor.- 3. Ultraviolet Irradiation.- 4. Tumour Promoters.- II. Polyamines and Hyperproliferative Diseases of the Skin.- 1. Psoriasis.- 2. Skin Cancers.- References.- 27 Proteolytic Enzymes in Relation to Skin Inflammation.- A. Introduction.- B. Proteases of the Skin.- I. Classification.- 1. Proteinases.- 2. Exopeptidases.- II. Cellular Localisation and Functions.- 1. Localisation.- 2. Functions.- C. Proteases in Inflammatory Cells.- I. Granulocytes.- II. Macrophages.- III. Other Inflammatory Cells.- D. Plasma-Derived Proteases.- E. Protease Inhibitors and Enhancers.- I. Plasma-Derived Inhibitors.- II. Inhibitors in Skin.- III. Protease Enhancers.- F. Proteases in Different Phases of Inflammation.- I. Vasodilatation and Exudation.- II. Chemotaxis.- III. Fibrin Deposition and Fibrinolysis.- IV. Repair and Chronic Inflammation.- 1. Repair.- 2. Chronic Inflammation.- G. Inflammatory Skin Conditions.- I. Immune Reactions.- II. Psoriasis.- III. Infections.- IV. Ionising Irradiation and Ultraviolet Light.- 1. Ionising Irradiation.- 2. Ultraviolet Light.- 3. Porphyria.- H. Deficiencies of Proteases and Their Inhibitors.- I. Protease Deficiencies.- II. Inhibitor Deficiencies.- J. Proteases and Pharmaceutical Agents.- K. Conclusion.- References.- 28 The Inflammatory Response - A Review.- A. Introduction.- B. Mediators of Vascular Changes.- C. Mediators of Cellular Responses.- I. Adhesion.- II. Chemotaxis and Leucocyte Migration Inhibition.- III. Phagocytosis and Release of Inflammatory Mediators.- References.- 29 Specific Acute Inflammatory Responses.- A. Introduction.- B. Immediate Weal and Flare Responses.- I. Responses to Intradermal Antigen Injection.- II. The Urticarias.- 1. Physical Urticarias.- 2. Chronic Idiopathic Urticaria and Angio-Oedema.- C. Delayed Acute Inflammation.- I. Ultraviolet Inflammation.- 1. Ultraviolet B Radiation.- 2. UV-C Irradiation.- 3. UV-A Irradiation.- II. Photochemotherapy (PUVA) Erythema.- III. Heat-Induced Inflammation.- IV. Trafuril (Tetrahydrofurfurylnicotinate).- V. Contact Allergic Dermatitis.- VI. Primary Irritant Dermatitis.- VII. Atopic Dermatitis.- VIII. Psoriasis.- References.

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