Implications of the Blood-Brain Barrier and Its Manipulation

Disruption in the Treatment of Brain Tumors: Animal Studies.- 1. Introduction.- 1.1. Basic Concept of the Blood-Brain Barrier in Tumors.- 1.2. Regulation of Drug Entry into the Central Nervous System.- 1.3. Osmotic Disruption of the Blood-Brain Barrier.- 1.4. Animal Models of Osmotic Blood-Brain Barrier Disruption.- 1.5. Reversibility of Osmotic Disruption.- 1.6. Pathologic and Behavioral Sequelae after Blood-Brain Barrier Disruption.- 2. Animal Studies of Osmotic Blood-Brain Barrier Disruption.- 2.1. Factors Affecting Blood-Brain Barrier Disruption and Drug Delivery.- 2.2. Drug Delivery after Blood-Brain Barrier Disruption.- 2.3. Drug Clearance from Brain after Blood-Brain Barrier Disruption.- 2.4. Monitoring Blood-Brain Barrier Disruption.- 2.5. Neurotoxicity of Chemotherapeutic Agents.- 2.6. Animal Models of Intracerebral Tumor Xenografts.- 2.7. Monoclonal Antibody Delivery to the Central Nervous System after Blood-Brain Barrier Disruption.- 2.8. Monoclonal Antibody Delivery to Intracerebral Tumors.- 2.9. Summary and Future Directions in Experimental Brain Tumor Therapy.- References.- 17B. Blood-Brain Barrier Disruption in the Treatment of Brain Tumors: Clinical Implications.- 1. Introduction.- 2. Clinical Trials of Osmotic BBB Modification in Patients with Malignant Brain Tumors.- 2.1. Technique of Osmotic BBB Modification.- 2.2. Monitoring of Methotrexate Delivery after Osmotic BBB Modification.- 2.3. Documentation of Osmotic BBB Modification by Enhanced CT Scanning.- 2.4. Documentation of Osmotic BBB Modification by Radionuclide Brain Scanning.- 3. Phase II (Efficacy) Studies of Chemotherapy Administered in Conjunction with Osmotic BBB Modification: Current Protocol and Regimen.- 3.1. Results in Patients with Glioblastoma.- 3.2. Results in Patients with Brain Metastases.- 3.3. Results in Patients with Primary CNS Lymphoma.- 3.4. Neurologic and Nonneurologic Complications Associated with Combination Chemotherapy and Osmotic BBB Modification.- 3.5. Maculopathy Associated with Combination Chemotherapy and Osmotic BBB Modification.- 4. Implications for Infusion of Tumor-Specific MAbs in Conjunction with Osmotic BBB Modification.- 4.1. Permeability of Human Brain Tumor to [99mTc]-GH and Albumin.- 4.2. Results of Radiolabeled MAb Delivery to Patients with Melanoma Metastatic to the Brain.- 5. Summary and Conclusions.- References.- 18. Bacterial and Fungal Brain Abscess and the Blood-Brain Barrier.- 1. Introduction.- 2. Clinical Studies.- 3. Experimental Brain Abscess Production.- 4. Imaging of Brain Abscess.- 4.1. Correlation of CT and Neuropathologic Findings.- 4.2. Ultrasound and Brain Abscess.- 4.3. Magnetic Resonance Imaging.- 4.4. Imaging of an Immunocompromised Host.- 5. The BBB and Antibiotic Delivery to Brain and Brain Abscess.- 6. Methods to Disrupt the Blood-Brain Barrier.- 7. Pharmacologic Animal Studies.- 8. Natural History of Brain Abscess in the Rodent.- 9. Differential Permeability of Brain Abscess to Antibiotics versus Antibody.- 10. Fungal Brain Abscess.- 11. Conclusion.- References.- 19. Genetic Enzyme Deficiencies and the Blood-Brain Barrier.- 1. Introduction.- 2. The Significance of Developing an Effective Therapy for Genetic Enzyme Deficiencies.- 3. The Rationale for Various Treatment Strategies.- 4. Problems Associated with Enzyme-Replacement Therapy.- 4.1. Delivery of Enzyme.- 4.2. Production of Enzyme.- 4.3. Protectionof Enzyme.- 4.4. Evaluation of Proposed Therapeutic Strategies.- 5. Past Experiences and Future Possibilities.- 5.1. Direct Replacement of Purified Exogenous Enzyme.- 5.2. Tissue Transplantation as a Means of Enzyme-Replacement Therapy.- 5.3. Replacement of the Gene Coding for the Defective Enzyme.- 6. Conclusion.- References.- 20. The Blood-Brain Barrier and Movement Disorders.- 1. Introduction.- 2. Parkinsonism and Dopaminergic Neurotransmission.- 2.1. Evidence That Parkinsonism Is a Dopamine Deficiency Disorder.- 2.2. Therapeutic Problems.- 2.3. Precursor Therapy.- 2.4. Lipophilic Dopaminergic Agents.- 2.5. Alternative Routes of Administration.- 2.6. Transplantation.- 3. Myoclonus and Serotonergic Neurotransmission.- 3.1. Myoclonus as a Serotonin Deficiency Disorder.- 3.2. Tryptophan and 5-Hydroxytryptophan as Serotonin Precursors.- 3.3. Therapeutic Results.- 4. Chorea, Memory Deficits, and Cholinergic Neurotransmission.- 4.1. Choreic Syndromes and Memory as Acetylcholine Deficiency Disorders.- 4.2. Choline and Lecithin as Acetylcholine Precursors.- 4.3. Diaminoethanol as an Acetylcholine Precursor.- 4.4. Therapeutic Results.- 5. Conclusion.- References.- 21. Chemoradiotherapy Interactions and the Blood-Brain Barrier.- 1. The Clinical Problem.- 1.1. Epidemiology of CNS Tumors and Brain Metastases.- 1.2. Limitations of Cerebrospinal Fluid Chemotherapy.- 1.3. Attempts to Combine Radiotherapy and Chemotherapy.- 1.4. Previous Reviews in Literature.- 2. Laboratory Studies.- 2.1. Radiation Factors.- 2.2. Methotrexate.- 2.3. Cytosine Arabinoside.- 2.4. Other Drugs.- 2.5. Summary.- 3. Clinical Studies.- 3.1. Lack of Evidence for Therapeutic Synergism of Chemoradiotherapy.- 3.2. Methotrexate.- 3.3. Cytosine Arabinoside.- 3.4. Other Drugs.- 3.5. Temporal Factors.- 3.6. Summary.- 4. Future Perspectives.- 4.1. Measures to Increase Therapeutic Efficacy.- 4.2. Measures to Decrease Neurotoxicity.- References.- 22. Hypertension and the Blood-Brain Barrier.- 1. Introduction.- 2. Acute Hypertension.- 2.1. Experimental Models.- 2.2. Why Does It Leak?.- 2.3. Modifying Factors.- 2.4. Neurogenic Influences.- 3. Chronic Hypertension.- 3.1. Renal Hypertension.- 3.2. Genetic Hypertension.- 4. Consequences and Clinical Implications.- 4.1. Potential Risk Situations for Hypertensive Opening of the BBB.- 4.2. Possible Acute and Chronic Effects of Transient BBB Opening.- 4.3. Hypertension and Brain Edema.- 4.4. Acute Hypertensive Encephalopathy.- 4.5. Degenerative Vascular Lesions in Chronic Hypertension.- 4.6. Cerebral Lacunes.- 4.7. Binswanger Encephalopathy.- 5. Summary and Conclusions.- References.- 23. Meningitis, Antimicrobial Agents, and the Blood-Brain Barrier.- 1. Introduction.- 2. Role of the Blood-Brain Barrier in Pathogenesis.- 2.1. Routes of Invasion.- 2.2. Protection of Meninges by the Blood-Brain Barrier.- 2.3. Age-Related Susceptibility.- 2.4. Possible Mechanisms of Invasion.- 3. Effect of Meningitis on the Blood-Brain Barrier.- 3.1. Increased Permeability.- 3.2. Pathologic Findings.- 3.3. CSF Leukocytosis.- 3.4. Containment of Infection.- 3.5. Hypoglycorrhachia.- 4. Importance of Achieving Cidal Concentrations of Antimicrobial Agents in CSF during Therapy for Meningitis.- 4.1. Need for Cidal Concentrations in CSF.- 4.2. Experimental Demonstration.- 4.3. Clinical Evidence.- 4.4. Optimum CSF Concentrations of Antimicrobial Agents.- 5. Factors Affecting Penetration of Antimicrobial Agents into CSF.- 5.1. Physicochemical Properties.- 5.2. Transport Mechanisms and Inhibitors.- 5.3. Experimental Methodology and Drug Kinetics.- 5.4. Osmotic Disruption of the Blood-Brain Barrier.- 5.5. Corticosteroid Therapy.- 6. Penetration of Antimicrobial Agents into CSF.- 6.1. Overview.- 6.2. ?-Lactam Antibiotics.- 6.3. Aminoglycoside Antibiotics.- 6.4. Chloramphenicol.- 6.5. Lincosamide Antibiotics.- 6.6. Tetracycline Antibiotics.- 6.7. Metronidazole.- 6.8. Sulfonamides and Trimethoprim.- 6.9. Vancomycin.- 6.10. Macrolide Antibiotics.- 6.11. Polypeptide Antibiotics.- 6.12. Antituberculous Agents.- 6.13. Antifungal Agents.- 7. Therapy for Meningitis.- 8. Summary and Conclusions.- References.- 24. Viral Infections and the Blood-Brain Barrier.- 1. Introduction.- 2. Mechanisms of Viral Passage across the Blood-Brain Barrier.- 2.1. The Neural Route.- 2.2. The Olfactory Route.- 2.3. The Hematogenous Route.- 3. Immune Responses to Viral Infection of the CNS.- 3.1. Local Antibody Synthesis.- 3.2. Effects of Immunosuppression.- 4. Blood-Brain Barrier Alterations in Experimental CNS Viral Infections.- 4.1. Sindbis Virus.- 4.2. Herpes Simplex Virus.- 4.3. Lymphocytic Choriomeningitis Virus.- 5. Blood-Brain Barrier Alterations in Human CNS Viral Infections.- 5.1. Herpes Simplex Encephalitis.- 5.2. AIDS Dementia Complex.- 6. CNS Antiviral Therapy.- 6.1. Nucleoside Analogues.- 6.2. Interferons.- 6.3. Immunoglobulins.- 7. Summary.- References.- 25. CNS Lupus and the Blood-Brain Barrier.- 1. Introduction.- 2. Neuropsychiatric Manifestations in Systemic Lupus Erythematosus.- 3. The Blood-Brain Barrier in CNS Lupus.- 3.1. The Blood-Brain Barrier and Blood-CSF Barrier.- 3.2. Neuropathology: Vascular Lesions.- 3.3. Blood-Brain Barrier Permeability Changes.- 4. Conclusions.- 4.1. Speculations and Questions.- 4.2. Summary.- References.- 26. Cerebrovascular Disease and the Blood-Brain Barrier.- 1. Introduction.- 2. Biochemistry of Ischemia.- 3.Eicosanoids, Cerebrovascular Disease, and the Blood-Brain Barrier.- 4. Evaluation of Blood-Brain Barrier Permeability.- 5. Cerebral Ischemia and Cerebral Infarction.- 5.1. Middle Cerebral Artery Occlusion.- 5.2. Common Carotid Artery Occlusion.- 5.3. Global Ischemia.- 5.4. Clinical Perspective.- 6. Hypoxia/Anoxia.- 7. Embolization.- 8. Hypertension.- 9. Spontaneous Intracerebral Hemorrhage.- 10. Subarachnoid Hemorrhage.- 11. Vascular Malformations.- 12. Cerebral Venous Disease.- 13. Neonatal Cerebral Injury.- 14. Radiation Cerebral Damage.- 15. Other Cerebrovascular Conditions.- 15.1. Diabetes.- 15.2. Cerebral Arteritides.- 15.3. Migraine.- 15.4. Substance Abuse Vasculopathy.- 15.5. Binswanger Subacute Arteriosclerotic Encephalopathy.- 16. Conclusion.- References.- 27. Epileptic Seizures and the Blood-Brain Barrier.- 1. General Considerations Concerning the Integrity of the Blood-Brain Barrier.- 2. BBB Dysfunction during Seizures.- 2.1. Animal Studies.- 2.2. Relationship between CBF and the BBB during Seizures.- 2.3. BBB Dysfunction during Seizures: Mechanical and Chemical Determinants.- 2.4. BBB, CBF, and Regional Differences.- 2.5. Human Studies: Dynamic Findings.- 3. Clinical Implications.- References.- 28. Metabolic Disturbances of the Blood-Brain Barrier with Special Emphasis on Glucose and Amino Acid Transport.- 1. Glucose.- 1.1. General Consideration of Transport Mechanisms for Glucose across the Blood-Brain Barrier.- 1.2. Glucose Carrier Transport.- 1.3. Insulin Effect.- 1.4. Influence of Blood Flow and pH.- 1.5. Induction of Transport.- 1.6. Glucose Transfer in Galactosemia.- 1.7. Glucose Transfer during Ethanol Intoxication and Withdrawal.- 1.8. Glucose Transfer in Meningitis.- 2. Amino Acids.- 2.1. General Considerations of Transport of Amino Acids across the Blood-Brain Barrier.- 2.2. Role of a BBB in Hepatic Encephalopathy.- 2.3. Aminoacidurias.- 3. Miscellaneous.- 3.1. Kernicterus.- 3.2. Uremic Encephalopathy.- 3.3. Decompression Sickness.- 3.4. Disturbances of Electrolyte, Acid-Base, and Water Balance.- 3.5. Heavy Metals and the Blood-Brain Barrier.- 4. Summary.- 4.1. Glucose.- 4.2. Amino Acids.- 4.3. Miscellaneous.- References.- 29. Implantable Pumps to Deliver Drugs Directly into the CNS.- 1. Introduction.- 2. Rationale for Directly Bypassing the Blood-Brain Barrier.- 2.1. Drugs That Do Not Naturally Cross the Blood-Brain Barrier.- 2.2. Localization of Drug Effect.- 2.3. Avoidance of the Circulatory System.- 3. Applications of Chronic Central Nervous System Infusion.- 3.1. Intrathecal Morphine for Pain Relief in Cancer Patients.- 3.2. Intrathecal Baclofen for Spinal Cord Spasticity.- 3.3. CSF and Interstitial Infusion of Anticancer Drugs for Malignant Brain Tumors.- 3.4. Cholinergic Infusion for Alzheimer Disease.- 4. Future Clinical Applications.- 5. Summary.- References.