Abstract
Summary
The delivery of drugs to central nervous system (CNS) is a challenge in the
treatment of neurological disorders. Drugs may be administered directly into
the CNS or administered systematically (e.g., by intravenous injection) for
targeted action in the CNS. The major challenge to CNS drug delivery is the
blood-brain barrier (BBB), which limits the access of drugs to the brain
substance.
Advances in understanding of the cell biology of the BBB have opened new
avenues and possibilities for improved drug delivery to the CNS. Several
carrier or transport systems, enzymes, and receptors that control the
penetration of molecules have been identified in the BBB endothelium.
Receptor-mediated transcytosis can transport peptides and proteins across the
BBB. Methods are available to assess the BBB permeability of drugs at the
discovery stage to avoid development of drugs that fail to reach their target
site of action in the CNS.
Various strategies that have been used for manipulating the blood-brain
barrier for drug delivery to the brain include osmotic and chemical opening of
the blood-brain barrier as well as the use of transport/carrier systems. Other
strategies for drug delivery to the brain involve bypassing the BBB. Various
pharmacological agents have been used to open the BBB and direct invasive
methods can introduce therapeutic agents into the brain substance. It is
important to consider not only the net delivery of the agent to the CNS, but
also the ability of the agent to access the relevant target site within the
CNS. Various routes of administration as well as conjugations of drugs, e.g.,
with liposomes and nanoparticles, are considered. Some routes of direct
administration to the brain are non-invasive such as transnasal route whereas
others involve entry into the CNS by devices and needles such as in case of
intrathecal and intracerebroventricular delivery. Systemic therapy by oral and
parenteral routes is considered along with sustained and controlled release to
optimize the CNS action of drugs. Among the three main approaches to drug
delivery to the CNS - systemic administration, injection into CSF pathways,
and direct injection into the brain - the greatest developments is anticipated
to occur in the area of targeted delivery by systemic administration.
Many of the new developments in the treatment of neurological disorders will
be biological therapies and these will require innovative methods for
delivery. Cell, gene and antisense therapies are not only innovative
treatments for CNS disorders but also involve sophisticated delivery methods.
RNA interference (RNAi) as a form of antisense therapy is also described.
The role of drug delivery is depicted in the background of various therapies
for neurological diseases including drugs in development and the role of
special delivery preparations. Pain is included as it is considered to be a
neurological disorder. Cell and gene therapies will play an important role in
the treatment of neurological disorders in the future.
The method of delivery of a drug to the CNS has an impact on the drug' s
commercial potential. The market for CNS drug delivery technologies is
directly linked to the CNS drug market. Values are calculated for the total
CNS market and the share of drug delivery technologies. Starting with the
market values for the year 2008, projections are made to the years 2013 and
2018. The markets values are tabulated according to therapeutic areas,
technologies and geographical areas. Unmet needs for further development in
CNS drug delivery technologies are identified according to the important
methods of delivery of therapeutic substances to the CNS. Finally suggestions
are made for strategies to expand CNS delivery markets. Besides development of
new products, these include application of innovative methods of delivery to
older drugs to improve their action and extend their patent life.
Profiles of 70 companies involved in drug delivery for CNS disorders are
presented along with their technologies, products and 65 collaborations. These
include pharmaceutical companies that develop CNS drugs and biotechnology
companies that provide technologies for drug delivery. A number of cell and
gene therapy companies with products in development for CNS disorders are
included. References contains over 400 publications that are cited in the
report. The report is supplemented with 50 tables and 9 figures.
Table of Contents
0. Executive Summary
1. Basics of Drug Delivery to the Central Nervous System
- Introduction
- Historical evolution of drug delivery for CNS disorders
- Neuroanatomical and neurophysiological basis of drug delivery
- The cerebrospinal fluid
- The extracellular space in the brain
- Neurotransmitters
- Neuropharmacology relevant to drug delivery
- Introduction to neuropharmacology
- Pharmacokinetics
- Absorption and distribution of drugs
- Drug metabolism and elimination
- Pharmacodynamics
- Receptors
- Sites of drug action in the CNS
- Receptors coupled to guanine nucleotide binding proteins
- Acetylcholine receptor channels
- Dopamine receptors
- GABA receptor channels
- Glutamate receptor channels
- Non-competitive NMDA antagonists
- Serotonin receptors
- G-protein coupled receptors
- In vivo study of drug action in the CNS in human patients
- Electroencephalography
- Brain imaging
- Chronopharmacology as applied to the CNS
2. Blood Brain Barrier
- Introduction
- Features of the blood-brain barrier relevant to CNS drug delivery
- The neurovascular unit
- Functions of the BBB
- BBB as an anatomical as well as physiological barrier
- BBB as a biochemical barrier
- Genomics and proteomics of BBB
- Other neural barriers
- Blood-cerebrospinal fluid barrier
- Blood nerve barrier
- Blood-retinal barrier
- Blood-labyrinth barrier
- Passage of substances across the blood-brain barrier
- Transporters localized in the BBB
- Glucose transporter
- Amino acid transporters
- Ionic transporter
- Efflux transport systems
- BBB-specific enzymes
- Receptor-mediated transcytosis
- Lysophosphatidic acid-mediated increade in BBB permeability
- Folate transport system
- Molecular biology of the BBB
- Transport of peptides and proteins across the BBB
- Passage of leptin across the BBB
- Passage of cytokines across the BBB
- Passage of hormones across the BBB
- Passage of enzymes across the BBB
- Drugs that cross the BBB by binding to plasma proteins
- Current concepts of the permeability of the BBB
- Factors that increase the permeability of the BBB
- BBB disruption as adverse effect of vaccines for CNS disorders
- CNS disorders that affect the permeability of BBB
- Neurodegenerative disorders
- Mitochondrial encephalopathies
- Multiple sclerosis
- Central nervous system injuries
- Epilepsy
- Cerebrovascular disease
- Infections
- Autoimmune disorders
- Brain tumors
- Testing permeability of the BBB
- In vitro models of BBB
- In vivo study of BBB
- Brain imaging
- In silico prediction of BBB
- Relevance of the BBB penetration to pharmacological action
- BBB penetration and CNS drug screening
- CERENSESM
- Transthyretin monomer as a marker of blood-CSF barrier disruption
- Evaluation of BBB permeability by brain imaging
- Biomarkers of disruption of blood-brain barrier
- Future directions for research on the BBB
- Application of genomics and proteomics to the study of BBB
- Use of neural stem cells to construct the blood brain barrier
- Strategies to cross the BBB
3. Methods of Drug Delivery to the CNS
- Introduction
- Routes of drug delivery to the brain
- Delivery of drugs to the brain via the nasal route
- Nasal delivery of insulin-like growth factor-I
- Nasal delivery of midazolam
- Nasal delivery of hypocretin
- Intranasal administration of IFN beta-1b
- Nasal delivery of thyrotropin-releasing hormone by nanoconstructs
- Nasal delivery of neuroprotective drugs for stroke
- Transdermal drug delivery for neurological disorders
- Drug delivery to the brain via inner ear
- Invasive neurosurgical approaches
- Intraarterial drug delivery to the brain
- Direct injection into the CNS substance or CNS lesions
- Intraventricular injection of drugs
- Intrathecal drug delivery
- Retrograde delivery to the brain via the epidural venous system
- Devices for drug delivery to the CNS
- Strategies for drug delivery to the CNS across the BBB
- Increasing the permeability (opening) of the BBB
- Osmotic opening of the BBB
- Focal disruption of BBB by ultrasound
- Chemical opening of the BBB
- Cerebral vasodilatation to open the BBB
- Use of nitric oxide donors to open the BBB
- Manipulation of the sphingosine 1-phosphate receptor system
- Pharmacological strategies to facilitate transport across the BBB
- 2B-Trans"! technology with specific carrier protein
- ABC afflux transporters and penetration of the BBB
- Carrier-mediated drug delivery across the BBB
- Glutathione transporters for drug delivery across the BBB
- Glycosylation Independent Lysosomal Targeting
- Inhibition of P-glycoprotein to enhance drug delivery across the BBB
- Modification of the drug to enhance its lipid solubility
- Monoclonal antibody fusion proteins
- Neuroimmunophilins
- Peptide-mediated transport across the BBB
- Prodrug bioconversion strategies and their CNS selectivity
- Role of the transferrin-receptor system in CNS drug delivery
- Transport of small molecules across the BBB
- Transport across the BBB by short chain oligoglycerolipids
- Transvascular delivery across the BBB
- Trojan horse approach
- Use of receptor-mediated transocytosis to cross the BBB
- Cell-based drug delivery to the CNS
- Activated T lymphocytes
- Microglial cells
- Neural stem cells
- Drug delivery to the CNS by using novel formulations
- Crystalline formulations
- Liposomes
- Monoclonal antibodies
- Microspheres
- Microbeads
- Lipid-coated microbubbles
- Brain-targeted chemical delivery systems
- Nanotechnology-based drug delivery to CNS
- Nanoparticles for drug delivery to CNS
- Nanovesicles for transport across BBB
- Nanotechnology-based devices and implants for CNS
- Biochip implants for drug delivery to the CNS
- Controlled-release microchip
- Retinal implant chip
- Convection-enhanced delivery to the CNS
- Systemic administration of drugs for CNS effects
- Sustained and controlled release drug delivery to the CNS
- Fast dissolving oral selegiline
- Choice of the route of systemic delivery for effect on the CNS disorders
- Methods of delivery of biopharmaceuticals to the CNS
- Delivery of biopharmaceuticals across the BBB
- Methods of delivery of peptides for CNS disorders
- Challenges for delivery of peptides across the BBB
- Transnasal administration of neuropeptides
- Direct delivery of neuropeptides into the brain
- Alteration of properties of the BBB for delivery of peptides
- Molecular manipulations of peptides to facilitate transport into CNS
- CNS delivery of peptides via conjugation to biological carriers
- Delivery of conopeptides to the brain
- Delivery of neurotrophic factors to the nervous system
- Systemic administration of NTFs
- Delivery systems to facilitate crossing of the BBB by NTFs
- Use of microspheres for delivery of neurotrophic factors
- Intracerebroventricular injection
- Direct application of NTFs to the CNS
- Intrathecal administration
- Implants for delivery of neurotrophic factors
- Use of neurotrophic factor mimics
- Use of microorganisms for therapeutic entry into the brain
- Bacteriophages as CNS therapeutics
- Intracellular drug delivery in the brain
- Local factors in the brain affecting drug action
- Methods for testing drug delivery to the CNS
- Animal models for testing drug delivery
- Screening for drug-P-gp interaction at BBB
4. Delivery of Cell, Gene and Antisense Therapies to the CNS
- Introduction
- Cell therapy of neurological disorders
- Methods for delivering cell therapies in CNS disorders
- Encapsulated cells
- Genetically modified stem cells for metachromatic leukodystrophy
- CNS neotissue implant
- CNS delivery of cells by catheters
- Subarachnoid delivery of stem cells
- Intravascular administration
- Gene therapy techniques for the nervous system
- Introduction
- Methods of gene transfer to the nervous system
- AAV vector mediated gene therapy for neurogenetic disorders
- Ideal vector for gene therapy of neurological disorders
- Promoters of gene transfer
- Routes of delivery of genes to the nervous system
- Direct injection into CNS
- Introduction of the genes into cerebral circulation
- Introduction of genes into cerebrospinal fluid
- Intravenous administration of vectors
- Delivery of gene therapy to the peripheral nervous system
- Cell-mediated gene therapy of neurological disorders
- Neuronal cells
- Neural stem cells and progenitor cells
- Astrocytes
- Cerebral endothelial cells
- Implantation of genetically modified encapsulated cells into the brain
- Genetically modified bone marrow cells
- Nanoparticles as non-viral vectors for CNS gene therapy
- Companies involved in cell/gene therapy of neurological disorders
- Antisense therapy of CNS disorders
- Delivery of antisense oligonucleotides to the CNS
- Delivery of oligonucleotides cross the BBB
- Cellular delivery systems for oligonucleotides
- High-flow microinfusion into the brain parenchyma
- Systemic administration of peptide nucleic acids
- Introduction of antisense compounds into the CSF Pathways
- Intrathecal administration of antisense compounds
- Intracerebroventricular administration of antisense oligonucleotides
- Nanoparticle-based delivery of antisense therapy to the CNS
- Methods of delivery of ribozymes
- Delivery aspects of RNAi therapy of CNS disorders
- Delivery of siRNA to the CNS
- Future drug delivery strategies applicable to the CNS
5. Drug Delivery in the Treatment of CNS Disorders
- Parkinson' s disease
- Drug delivery systems for Parkinson' s disease
- Duodenal levodopa infusion
- Transdermal drug delivery for PD
- Transdermal dopamine agonists for Parkinson' s disease
- Transdermal administration of other drugs for Parkinson' s disease
- Intracerebral administration of GDNF
- Cell therapy for Parkinson' s disease
- Human dopaminergic neurons for PD
- Graft survival-enhancing drugs
- Xenografting porcine fetal neurons
- Encapsulated cells for PD
- Stem cells for PD
- Engineered stem cells for drug delivery to the brain in PD
- Human retinal pigment epithelium cells for PD
- Delivery of cells for PD
- Gene therapy for Parkinson disease
- Rationale
- Techniques of gene therapy for PD
- Prospects of gene therapy for Parkinson' s disease
- Companies developing gene therapy for PD
- RNAi therapy of Parkinson' s disease
- Alzheimer disease
- Drug delivery for Alzheimer disease
- Blood-brain partitioning of an AMPA receptor modulator
- Clearing amyloid through the BBB
- Delivery of the passive antibody directly to the brain
- Delivery of thyrotropin-releasing hormone analogs by molecular packaging
- Intranasal delivery of nerve growth factor to the brain
- Nanoparticle-based drug delivery for Alzheimer' s disease
- Perispinal etanercept
- Slow release implant of an AChE inhibitor
- Transdermal drug delivery in Alzheimer' s disease
- Trojan-horse approach to prevent build-up of Aβ aggregates
- Cell and gene therapy for Alzheimer disease
- NGF gene therapy
- Neprilysin gene therapy
- RNAi therapy of Alzheimer' s disease
- Huntington' s disease
- Treatment of Huntington' s disease
- Drug delivery in Huntington' s disease
- Gene therapy of Huntington' s disease
- Encapsulated genetically engineered cellular implants
- Viral vector mediated administration of neurotrophic factors
- RNAi therapeutics for the treatment of HD
- Amyotrophic lateral sclerosis
- Treatment of ALS
- Drug delivery in ALS
- Gene and antisense therapy of amyotrophic lateral sclerosis
- Neurotrophic factor gene therapies of ALS
- Antisense therapy of ALS
- RNAi therapy of amyotrophic lateral sclerosis
- Drug delivery for CNS involvement in Hunter syndrome
- Cerebrovascular disease
- Treatment of stroke
- Drug delivery in stroke
- Intraarterial administration of tissue plasminogen activator in stroke
- Drug delivery for prevention of restenosis of carotid arteries
- Modified NO donors
- In-stent restenosis
- Targeted local anti-restenotic drug delivery
- Catheter-based drug delivery for restenosis
- Stents for prevention of restenosis
- Drug-eluting stents
- Antisense approach to prevent restenosis
- Drug-eluting stents for the treatment of intracranial atherosclerosis
- Tissues transplants for stroke
- Transplant of encapsulated tissue secreting neurotrophic factors
- Cell therapy for stroke
- Stem cell transplant into the brain
- Immortalized cell grafts for stroke
- Intravenous infusion of marrow stromal cells
- Intravenous infusion of umbilical cord blood stem cells
- Future of cell therapy for stroke
- Gene therapy of cerebrovascular diseases
- Gene transfer to cerebral blood vessels
- NOS gene therapy for restenosis
- Gene therapy for cerebral ischemia
- Gene therapy of strokes with a genetic component
- Drug delivery to intracranial aneurysms
- Drug delivery for vasospasm following subarachnoid hemorrhage
- Intrathecal tissue plasminogen activator
- Gene therapy for vasospasm
- Drug delivery in multiple sclerosis
- Oral therapies for MS
- Antisense and RNAi approaches to MS
- Cell therapy for multiple sclerosis
- Hematopoietic stem cell transplantation for multiple sclerosis
- Embryonic stem cells and neural precursor cells for MS
- Gene therapy for multiple sclerosis
- Drug delivery in epilepsy
- Routes of administration of antiepileptic drugs
- Controlled-release preparations of carbamazepine
- Various methods of delivery of diazepam
- Methods of delivery of novel antiepileptic therapies
- Regulated activation of prodrugs
- Use of neuronal membrane transporter
- Delivery of the antiepileptic conopeptides to the brain
- Nasal administration of AEDs
- Intracerebral administration of phenytoin
- The role of drug delivery in status epilepticus
- Cell therapy of epilepsy
- Gene therapy for epilepsy
- Gene therapy for neuroprotection in epilepsy
- Concluding remarks on drug delivery in epilepsy
- Drug delivery for pain
- Intranasal delivery of analgesics
- Intranasal administration of morphine
- Intranasal fentanyl
- Intranasal ketamine
- Delivery of analgesics by inhalation
- Spinal delivery of analgesics
- Epidural administration of encapsulated morphine
- Relief of pain by intrathecal ziconotide
- Intrathecal neostigmine
- Intrathecal prostaglandin antagonists
- Intrathecal non-NMDA antagonists
- Intrathecal siRNA for relief of neuropathic pain
- Intracerebroventricular drug delivery for pain
- Delivery of analgesics to the CNS across the BBB
- Drug delivery for migraine
- Management of migraine
- Novel drug delivery methods for migraine
- Nasal formulations for migraine
- Sublingual spray for migraine
- Needle-free drug delivery for migraine
- Relief of spasticity by intrathecal baclofen
- Drug delivery for brain tumors
- Methods for evaluation of anticancer drug penetration into brain tumor
- Innovative methods of drug delivery for glioblastoma multiforme
- Anticancer agents with increased penetration of BBB
- Local delivery of chemotherapeutic agents into the tumor
- Carmustine biodegradable polymer implants
- Fibrin glue implants containing anticancer drugs
- Biodegradable microspheres containing 5-FU
- Nanoparticles for delivery of drugs to brain tumors across BBB
- Convection-enhanced delivery
- Delivery of antibody-based anticancer therapy by ultrasound BBB disruption
- Targeted monoclonal antibodies conjugated with liposomes
- Immunoliposomes
- Lipid-coated microbubbles as a delivery vehicle for taxol
- Thermoliposomes containing cytotoxic drugs
- Introduction of the chemotherapeutic agent into the CSF pathways
- Intrathecal chemotherapy
- Intraventricular chemotherapy for meningeal cancer
- Increasing the permeability of blood-tumor barrier to anticancer drugs
- Disruption of BBB
- Nanoparticle-based targeted delivery of chemotherapy across the BBB
- Modulating efflux transporters to enhance chemotherapy penetration
- PDE5 inhibitors for enhancing tumor permeability to chemotherapy
- Intra-arterial chemotherapy
- Interstitial delivery of dexamethasone for reduction of peritumor edema
- Photodynamic therapy for chemosensitization
- Boron neutron capture therapy
- Gene therapy for glioblastoma multiforme
- Single-chain antibody-targeted adenoviral vectors
- Peptides targeted to glial tumor cells
- Antiangiogenic gene therapy
- RNAi gene therapy of brain cancer
- Drug delivery for traumatic brain injury
- Cell therapy of traumatic brain injury
- Gene therapy for traumatic brain injury
- Drug delivery for spinal cord injury
- Administration of neurotrotrophic factors for spinal cord injury
- Cell therapy for spinal cord injury
- Transplantation of glial cells for SCI
- Fetal neural grafts for SCI
- Embryonic stem cells for SCI
- Schwann cell transplants for SCI
- Olfactory glial cells for SCI
- Marrow stromal cells for SCI
- Intravenous injection of stem cells for spinal cord repair
- Combinatorial approach for regeneration in SCI
- Cell therapy of syringomyelia
- Gene therapy of spinal cord injury
- Drug delivery for retinal disorders
- Age-related macular degeneration
- TheraSight ocular brachytherapy system for wet AMD
- Combretastatin A4P for myopic macular degeneration
- Gene therapy for AMD
- Anti-VEGF approach to AMD
- Delivery of aptamers for treatment of AMD
- Stem cell therapy for retinitis pigmentosa
- Proliferative retinopathies
- Drug delivery in CNS infections
- Drug delivery in neuroAIDS
6. Markets for Drug Delivery in CNS Disorders
- Introduction
- Methods of calculation of CNS drug delivery markets
- Markets for CNS drug delivery technologies
- Drug delivery share in selected CNS markets
- CNS share of drug delivery technologies
- Geographical distribution of CNS drug delivery markets
- Impact of improved drug delivery on CNS drug markets
- Neurodegenerative disorders
- Alzheimer' s disease
- Parkinson' s Disease
- Huntington' s disease
- Amyotrophic lateral sclerosis
- Epilepsy
- Migraine and other headaches
- Stroke
- Spinal cord injury
- Multiple sclerosis
- Brain tumors
- Limitations of the current drug delivery technologies for CNS
- Unmet needs in CNS drug delivery technologies
- Future strategies for expanding CNS drug delivery markets
- Education of neurologists
- Demonstration of the advantages of the newer methods of delivery
- Rescue of old products by novel drug delivery methods
- Facilitation of the approval process of new drugs
7. Companies
- Introduction
- Profiles
- Collaborations
8. References
Tables
- Table 1 1: Landmarks in the development of drug delivery to the CNS
- Table 2 1: Proteins expressed at the neurovascular unit
- Table 2 2: Transporters that control penetration of molecules across the
BBB
- Table 2 3: Enzymes that control the penetration of molecules across the BBB
- Table 2 4: Factors that increase the permeability of the BBB
- Table 2 5: Diseases that affect the BBB
- Table 3 1: Various methods of drug delivery to the central nervous system
- Table 3 2: Drugs available for intrathecal administration
- Table 3 3: Strategies for drug delivery to the CNS across the BBB
- Table 3 4: Specific inhibitors of P-glycoprotein in clinical development
- Table 3 5: Molecules attached to Trojan horses injected intravenously for
CNS effect
- Table 3 6: Examples of controlled and sustained release drug delivery for
CNS disorders
- Table 3 7: Novel methods of delivery of drugs for CNS disorders
- Table 3 8: Indications for the clinical applications of NTFs in neurologic
disorders
- Table 3 9: Methods for delivery of neurotrophic factors to the CNS
- Table 4 1: Methods for delivering cell therapies in CNS disorders
- Table 4 2: Classification of methods of gene therapy
- Table 4 3: Methods of gene transfer as applied to neurologic disorders
- Table 4 4: Companies developing cell/gene therapies for CNS disorders
- Table 4 5: Methods of antisense delivery as applied to the CNS
- Table 5 1: Strategies for the treatment of Parkinson' s disease
- Table 5 2: Drug delivery systems for Parkinson' s disease
- Table 5 3: Types of cell used for investigative treatment of Parkinson' s
disease
- Table 5 4: Status of cell therapies in development for Parkinson' s disease
- Table 5 5: Gene therapy techniques applicable to Parkinson disease
- Table 5 6: Companies developing gene therapy for Parkinson' s disease
- Table 5 7: Classification of pharmacotherapy for Alzheimer disease
- Table 5 8: Novel drug delivery methods for Alzheimer disease therapies
- Table 5 9: Classification of neuroprotective agents for amyotrophic
lateral sclerosis
- Table 5 10: Methods of delivery of therapies in development for ALS
- Table 5 11: Classification of treatments for stroke
- Table 5 12: Treatments of stroke involving innovative drug delivery methods
- Table 5 13: Drug delivery for prevention of carotid artery restenosis
after angioplasty
- Table 5 14: Gene transfer in animal models of carotid artery restenosis
- Table 5 15: Neuroprotective gene transfer strategies in models of cerebral
ischemia
- Table 5 16: Gene Therapy for reducing cerebral infarction in animal stroke
models
- Table 5 17: Pharmacological agents for treatment of cerebral vasospasm
- Table 5 18: Gene therapy strategies for vasospasm
- Table 5 19: A classification of drug delivery methods used in management
of pain
- Table 5 20: Spinal/intrathecal administration of drugs for pain
- Table 5 21: Investigational drugs for pain administered by intrathecal
route
- Table 5 22: Current management of migraine
- Table 5 23: Novel drug delivery methods for migraine
- Table 5 24: Innovative methods of drug delivery for glioblastoma multiforme
- Table 5 25: Strategies for gene therapy of malignant brain tumors
- Table 6 1: Share of drug delivery technologies in selected CNS markets:
2008-2018
- Table 6 2: CNS market share of drug delivery technologies 2008-2018
- Table 6 3: Value of CNS drug delivery in the major world markets from
2008-2018
- Table 6 4: Limitations of the current drug delivery technologies for CNS
- Table 7 1: Collaborations of companies in CNS drug delivery
Figures
- Figure 1 1: Interaction of neurotransmitters with receptors
- Figure 2 1: The neurovascular unit
- Figure 2 2: Various forms of passage of substances across the blood brain
barrier
- Figure 3 1: Routes of drug delivery to the brain
- Figure 3 2: Use of receptor-mediated transcytosis to cross the BBB
- Figure 5 1: Oral versus transdermal administration of a drug in
Parkinson' s disease
- Figure 5 2: Effect of tyrosine hydroxylase gene delivery on dopamine levels
- Figure 5 3: A concept of targeted drug delivery to GBM across the BBB
- Figure 6 1: Unmet needs in the CNS drug delivery technologies
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