We are searching data for your request:
Upon completion, a link will appear to access the found materials.
I have just started reading up on structure-based methods for drug design (this is completely not my field so apologies for stupid questions that will be coming along!)
Clearly, some drugs are designed to target the central nervous system. However, I understand that the extracellular fluid of the central nervous system is separated from the blood by the "blood-brain barrier" which restricts the passage of large molecules between the two systems.
My question is : how do you design a drug to be delivered to the CNS?
In a nutshell: in order to pass through the blood-brain barrier (BBB) the substance has to mimick soee properties of the substances that are allowed to pass through.
There are different types of "transporters" -- integral proteins going through the cell membranes and accounting for the active transport of the substances they can actively bind to. Smaller molecules of drugs can use solute carrier transporter (SLC), whereas bigger molecules (oligo- and polymeres) would use the receptor-mediated transporter (RMT).
There is a nice article on this topic published by ScienceDaily.
Here is the quote:
One technology for enabling active transport of small molecule drugs across the BBB involves targeting endogenous nutrient transporters. These transporters are members of the solute carrier (SLC) transporter superfamily. Transport of small molecules across the BBB by these membrane proteins is known as carrier-mediated transport (CMT).
In order to design drugs that utilize CMT to cross the BBB, researchers modify their chemical structures so that they resemble nutrients that are transported across the BBB by specific SLCs. The prototypical drug that uses this strategy (which was developed long before mechanisms of CMT were known) is L-DOPA, the major current drug for Parkinson's disease. L-DOPA is used to replace dopamine that is lost due to degeneration of dopaminergic neurons in the substantia nigra of the brain.
Another major system that is used in normal mammalian physiology to enable needed molecules to cross the BBB is receptor-mediated transport (RMT). The brain uses RMT to transport proteins, peptides, and lipoproteins that are needed for brain function across the BBB. Examples of biomolecules that are transported into the brain via RMT include insulin, insulin-like growth factor (IGF), leptin, transferrin, and low-density lipoprotein (LDL).
In RMT, molecules in the circulation may bind to specific receptors on the luminal surface of brain capillaries (i.e., the surface that interfaces with the bloodstream). Upon binding, the receptor-ligand complex is internalized into the endothelial cell by a process called receptor-mediated endocytosis. The ligand may then be transported across the abluminal membrane of the endothelial cell (i.e., the membrane that interfaces with brain tissue) into the brain. This whole process is called receptor-mediated transcytosis.
The blood–brain barrier is formed by special tight junctions between endothelial cells lining brain blood vessels. Blood vessels of all tissues contain this monolayer of endothelial cells, however only brain endothelial cells have tight junctions preventing passive diffusion of most substances into the brain tissue.  The structure of these tight junctions was first determined in the 1960s by Tom Reese, Morris Kranovsky and Milton Brightman. Furthermore, astrocytic "end feet", the terminal regions of the astrocytic processes, surround the outside of brain capillary endothelial cells".  The astrocytes are glial cells restricted to the brain and spinal cord and help maintain blood-brain barrier properties in brain endothelial cells. 
The main function of the blood–brain barrier is to protect the brain and keep it isolated from harmful toxins that are potentially in the blood stream. It accomplishes this because of its structure, as is usual in the body that structure defines its function. The tight junctions between the endothelial cells prevent large molecules as well as many ions from passing between the junction spaces. This forces molecules to go through the endothelial cells in order to enter the brain tissue, meaning that they must pass through the cell membranes of the endothelial cells.  Because of this, the only molecules that are easily able to transverse the blood–brain barrier are ones that are very lipid-soluble. These are not the only molecules that can transverse the blood–brain barrier glucose, oxygen and carbon dioxide are not lipid-soluble but are actively transported across the barrier, to support normal cellular function of the brain.  The fact that molecules have to fully transverse the endothelial cells makes them a perfect barricade to unspecified particles from entering the brain, working to protect the brain at all costs. Also, because most molecules are transported across the barrier, it does a very effective job of maintaining homeostasis for the most vital organ of the human body. 
Because of the difficulty for drugs to pass through the blood–brain barrier, a study was conducted to determine the factors that influence a compound’s ability to transverse the blood–brain barrier. In this study, they examined several different factors to investigate diffusion across the blood–brain barrier. They used lipophilicity, Gibbs Adsorption Isotherm, a Co CMC Plot, and the surface area of the drug to water and air. They began by looking at compounds whose blood–brain permeability was known and labeled them either CNS+ or CNS- for compounds that easily transverse the barrier and those that did not.  They then set out to analyze the above factors to determine what is necessary to transverse the blood–brain barrier. What they found was a little surprising lipophilicity is not the leading characteristic for a drug to pass through the barrier. This is surprising because one would think that the most effective way to make a drug move through a lipophilic barrier is to increase its lipophilicity, it turns out that it is a complex function of all of these characteristics that makes a drug able to pass through the blood–brain barrier. The study found that barrier permittivity is "based on the measurement of the surface activity and as such takes into account the molecular properties of both hydrophobic and charged residues of the molecule of interest."  They found that there is not a simple answer to what compounds transverse the blood–brain barrier and what does not. Rather, it is based on the complex analysis of the surface activity of the molecule as well as relative size.
Other problems persist besides just simply getting through the blood–brain barrier. The first of these is that a lot of times, even if a compound transverses the barrier, it does not do it in a way that the drug is in a therapeutically relevant concentration.  This can have many causes, the most simple being that the way the drug was produced only allows a small amount to pass through the barrier. Another cause of this would be the binding to other proteins in the body rendering the drug ineffective to either be therapeutically active or able to pass through the barrier with the adhered protein.  Another problem that must be accounted for is the presence of enzymes in the brain tissue that could render the drug inactive. The drug may be able to pass through the membrane fine, but will be deconstructed once it is inside the brain tissue rendering it useless. All of these are problems that must be addressed and accounted for in trying to deliver effective drug solutions to the brain tissue. 
Exosomes to deliver treatments across the blood–brain barrier Edit
A group from the University of Oxford led by Prof. Matthew Wood claims that exosomes can cross the blood–brain barrier and deliver siRNAs, antisense oligonucleotides, chemotherapeutic agents and proteins specifically to neurons after inject them systemically (in blood). Because these exosomes are able to cross the blood–brain barrier, this protocol could solve the issue of poor delivery of medications to the central nervous system and cure Alzheimer's, Parkinson's Disease and brain cancer, among other diseases. The laboratory has been recently awarded a major new €30 million project leading experts from 14 academic institutions, two biotechnology companies and seven pharmaceutical companies to translate the concept to the clinic.    
This is the process of disguising medically active molecules with lipophilic molecules that allow it to better sneak through the blood–brain barrier. Drugs can be disguised using more lipophilic elements or structures. This form of the drug will be inactive because of the lipophilic molecules but then would be activated, by either enzyme degradation or some other mechanism for removal of the lipophilic disguise to release the drug into its active form. There are still some major drawbacks to these pro-drugs. The first of which is that the pro-drug may be able to pass through the barrier and then also re-pass through the barrier without ever releasing the drug in its active form. The second is the sheer size of these types of molecules makes it still difficult to pass through the blood–brain barrier. 
Peptide masking Edit
Similar to the idea of pro-drugs, another way of masking the drugs chemical composition is by masking a peptide’s characteristics by combining with other molecular groups that are more likely to pass through the blood–brain barrier. An example of this is using a cholesteryl molecule instead of cholesterol that serves to conceal the water soluble characteristics of the drug. This type of masking as well as aiding in traversing the blood–brain barrier. It also can work to mask the drug peptide from peptide-degrading enzymes in the brain  Also a "targetor" molecule could be attached to the drug that helps it pass through the barrier and then once inside the brain, is degraded in such a way that the drug cannot pass back through the brain. Once the drug cannot pass back through the barrier the drug can be concentrated and made effective for therapeutic use.  However drawbacks to this exist as well. Once the drug is in the brain there is a point where it needs to be degraded to prevent overdose to the brain tissue. Also if the drug cannot pass back through the blood–brain barrier, it compounds the issues of dosage and intense monitoring would be required. For this to be effective there must be a mechanism for the removal of the active form of the drug from the brain tissue. 
Receptor-mediated permabilitizers Edit
These are drug compounds that increase the permeability of the blood–brain barrier.  By decreasing the restrictiveness of the barrier, it is much easier to get a molecule to pass through it. These drugs increase the permeability of the blood–brain barrier temporarily by increasing the osmotic pressure in the blood which loosens the tight junctions between the endothelial cells. By loosening the tight junctions normal injection of drugs through an [IV] can take place and be effective to enter the brain.  This must be done in a very controlled environment because of the risk associated with these drugs. Firstly, the brain can be flooded with molecules that are floating through the blood stream that are usually blocked by the barrier. Secondly, when the tight junctions loosen, the homeostasis of the brain can also be thrown off which can result in seizures and the compromised function of the brain. 
The most promising drug delivery system is using nanoparticle delivery systems, these are systems where the drug is bound to a nanoparticle capable of traversing the blood–brain barrier. The most promising compound for the nanoparticles is Human Serum Albumin (HSA). The main benefits of this is that particles made of HSA are well tolerated without serious side effects as well as the albumin functional groups can be utilized for surface modification that allows for specific cell uptake.  These nanoparticles have been shown to transverse the blood–brain barrier carrying host drugs. To enhance the effectiveness of nanoparticles, scientists are attempting to coat the nanoparticles to make them more effective to cross the blood–brain barrier. Studies have shown that "the overcoating of the [nanoparticles] with polysorbate 80 yielded doxorubicin concentrations in the brain of up to 6 μg/g after i.v. injection of 5 mg/kg" as compared to no detectable increase in an injection of the drug alone or the uncoated nanoparticle.  This is very new science and technology so the real effectiveness of this process has not been fully understood. However young the research is, the results are promising pointing to nanotechnology as the way forward in treating a variety of brain diseases.
Loaded microbubble-enhanced focused ultrasound Edit
Microbubbles are small "bubbles" of mono-lipids that are able to pass through the blood–brain barrier. They form a lipophilic bubble that can easily move through the barrier.  One barrier to this however is that these microbubbles are rather large, which prevents their diffusion into the brain. This is counteracted by a focused ultrasound. The ultrasound increases the permeability of the blood–brain barrier by causing interference in the tight junctions in localized areas. This combined with the microbubbles allows for a very specific area of diffusion for the microbubbles, because they can only diffuse where the ultrasound is disrupting the barrier.  The hypothesis and usefulness of these is the possibility of loading a microbubble with an active drug to diffuse through the barrier and target a specific area.  There are several important factors in making this a viable solution for drug delivery. The first is that the loaded microbubble must not be substantially greater than the unloaded bubble. This ensures that the diffusion will be similar and the ultrasound disruption will be enough to induce diffusion. A second factor that must be determined is the stability of the loaded micro-bubble. This means is the drug fully retained in the bubble or is there leakage. Lastly, it must be determined how the drug is to be released from the microbubble once it passes through the blood–brain barrier. Studies have shown the effectiveness of this method for getting drugs to specific sites in the brain in animal models. 
Central Nervous System Function
Coordination and Movement
The primary function of the central nervous system is integration and coordination. The CNS receives input from a variety of different sources, and implements an appropriate response to the stimuli, in a cohesive manner. For instance, in order to walk the CNS needs visual and integumentary cues – the texture of the surface, its incline, the presence of obstacles, and so forth.
Based on these stimuli, the CNS alters skeletal muscle contraction. Once infants learn to walk, this happens involuntarily, no longer requiring conscious thought or concentration. A similar process of receiving complex stimuli and generating a coordinated response is required for vastly varied activities – whether it is balancing a bicycle, maintaining a conversation or mounting an immune response.
Thought and Processing
The CNS directly or indirectly influences nearly every internal organ system, whether related to respiration, digestion, excretion, circulation or reproduction.
Hitching a lift: the Trojan horse approach
What about larger molecules &mdash such as the biologics that make up an increasing number of today&rsquos therapeutics? Can they get through the &lsquobrick wall&rsquo? Banks says many natural peptides and molecules such as insulin, transferrin and lipoproteins do pass through via regulated entry mechanisms &mdash a second aspect of the BBB&rsquos function. Regulated entry mechanisms use influx transporter proteins in the barrier. Macromolecules are then transported across cells in several ways, including transcytosis, where molecules are transported in vesicles.
Taking advantage of these mechanisms is the cornerstone of the Trojan horse approach. By attaching a therapeutic molecule to something that is transported across the BBB, the drug cargo can be smuggled through. However, it has not always been successful, says Banks. One of the first attempts was to use the glucose transport system. &ldquoPeople were putting really big molecules on [glucose] and it didn&rsquot work.&rdquo He jokes: &ldquoIt was like having a Volkswagen pull the space shuttle.&rdquo
Approaches today often use short amino acid chains called peptides as Trojan horses. In 2007, the first peptide was proven to transport drugs into the brain. The 29-amino-acid peptide RVG29 was derived from rabies virus glycoprotein (RVG) and was able to deliver a gene-silencing RNA (siRNA) molecule to the brain 
. Intravenous injection delivered the antiviral siRNA to neuronal cells in mice and, once inside, the payload provided protection against fatal viral encephalitis.
In the past five years, more than 30 BBB &lsquoshuttle&rsquo proteins have been identified and their efficiency and versatility is increasing. Organic chemist Ernest Giralt, at Barcelona&rsquos Institute for Research in Biomedicine, has put an interesting spin on the approach. He realised that some animal venoms are able to penetrate the CNS and looked at the bee venom peptide, apamin. By removing the chemical groups that block potassium channels, his team created a non-toxic peptide, Mini-Ap4, which was able to transport attached drugs through the BBB 
Marseille-based biotechnology company Vect-Horus has patents on several peptide Trojan horses, which it calls vectors, and has been working to optimise their ability to deliver drugs. The company started by selecting target receptors in the BBB and screened peptides to find the best matches, explains Jamal Temsamani, director of drug development for Vect-Horus. Proof of principle of its system for transporting a range of molecules has been demonstrated in animal models. Among them is the peptide neurotensin, which can induce therapeutic hypothermia for resuscitation after cardiac arrest or neonatal ischemia, but cannot pass the BBB. Using a peptide-vector, Vect-Horus has designed a conjugate (VH-N439) that is able to get into the brain. The compound is currently in regulatory preclinical studies.
Peptide shuttles seem promising, and pharmaceutical companies are taking notice, for example Vect-Horus has a current collaboration with Sanofi. But as Trippier points out: &ldquoThe major issue is their lack of generality, so they can take through one particular compound or one particular biologic, but they completely fail on different ones.&rdquo
Temsamani concedes: &ldquoThere is no unique vector that can be used as a universal brain delivery system&rdquo.
There are other approaches to getting drugs into the brain, such as looking at how particle structure at the nanoscale affects delivery. As with other drug delivery strategies, encapsulating drugs in nanoparticles aims to help deliver the drug to where it&rsquos needed before being degraded.
Nanomerics, a company founded by Ijeoma Uchegbu, a pharmaceutical nanoscientist at University College London, is concentrating on this approach. Its proprietary Molecular Envelope Technology (MET) nanoparticles are engineered from biocompatible polymers. They self assemble into highly stable 50nm nanoparticles that act as a protective molecular envelope for hydrophobic drugs and peptides hidden inside.
The nanoparticles themselves do not cross the BBB, they stick to the capillaries in the brain and then the drug has a longer time to diffuse across the epithelial cells
Source: Courtesy of Ijeoma Uchegbu
Ijeoma Uchegbu, a pharmaceutical nanoscientist at University College London and founder of Nanomerics, says nanoparticles stick to the capillaries in the brain allowing the drug longer to diffuse across the epithelial cells
The nanoparticles have shown potential in treating brain tumours which are currently attacked with very high levels of cytotoxic agents to get enough drug across the BBB. Using MET nanoparticles loaded with the chemotherapy drug Lomustine, Uchegbu was able to increase survival times in mice by about a third, compared with chemotherapy alone 
. She says: &ldquoThe nanoparticles themselves do not cross the BBB, they stick to the capillaries in the brain and then the drug has a longer time to diffuse across the epithelial cells.&rdquo A positive charge on the particles helps them stick, but Uchegbu can&rsquot yet explain why the particles seem to stick to the BBB but not other capillaries in the kidney or lungs.
Uchegbu is also using nanostructures to deliver peptides. An example is the peptide dalargin this synthetic opioid neurotransmitter has morphine-like activity, but is unable to penetrate the BBB. &ldquoWe derivatised the peptides to add a lipophilic anchor and this caused the peptide to self-assemble into, in this case, elongated fibres 500nm by 20nm,&rdquo she explains. &ldquoBecause their shape is changed, they seem to cross the endothelial barrier to the brain 
.&rdquo Using amphiphilic derivatives, with both hydrophilic and hydrophobic parts, peptides will self assemble into fibres that are tightly wrapped around a central hydrophobic core. In this form they resist degradation, improving their chances of getting to the brain. Uchegbu says it&rsquos not clear whether the particles cross the BBB as fibres or if they disassemble and are taken up as individual molecules.
Another approach to getting through the BBB is using exosomes, which, according to Banks, is &ldquothe hottest area right now and also the newest area&rdquo. Exosomes are tiny lipid bilayer-bound bubbles produced in cells &mdash they are the body&rsquos own transport vehicles. This method of transfer has been successfully tried in animal models of Parkinson&rsquos disease, using exosomes extracted from white blood cells. The exosomes were loaded with the enzyme catalase, a potent antioxidant that counters the neuron-killing inflammation responsible for Parkinson&rsquos 
. Several companies, are racing to exploit this technology, including an Oxford University spin-out EvOx, which recently raised a £10m investment.
Task - writing exercise
- a branch of science that deals with emotions
- the study of how drugs work
- the study of living things
- chemical in the brain
- gap between nerve cells
- nerve cell
- imitating neurotransmitters
- destroying brain cells
- creating dysfunctional neural pathways
- the distortion of electrochemical messages between neurons
- stimulation of pleasure centres in the brain
- elimination of withdrawal symptoms
- Group 1
- Group Name -
- Example 1 -
- Example 2 -
- Group name -
- Example 1 -
- Example 2 -
- Group name -
- Example 1 -
- Example 2 -
Central Nervous System Structure
The CNS has three main components: the brain, the spinal cord, and the neurons (or nerve cells).
The brain controls many of the body's functions including sensation, thought, movement, awareness, and memory. The surface of the brain is known as the cerebral cortex. The surface of the cortex appears bumpy thanks to the grooves and folds of the tissue. Each groove is known as a sulcus, while each bump is known as a gyrus.
The largest part of the brain is known as the cerebrum and is responsible for things such as memory, speech, voluntary behaviors, and thought.
The cerebrum is divided into two hemispheres, a right hemisphere, and a left hemisphere. The brain's right hemisphere controls movements on the body's left side, while the left hemisphere controls movements on the body's right side.
While some functions do tend to be lateralized, researchers have found that there are not "left brained" or "right brained" thinkers, as the old myth implies. Both sides of the brain work together to produce various functions.
- Frontal lobes are associated with higher cognition, voluntary movements, and language.
- Occipital lobes are associated with visual processes.
- Parietal lobes are associated with processing sensory information.
- Temporal lobes are associated with hearing and interpreting sounds as well as the formation of memories.
The spinal cord connects to the brain via the brain stem and then runs down through the spinal canal, located inside the vertebra. The spinal cord carries information from various parts of the body to and from the brain. In the case of some reflex movements, responses are controlled by spinal pathways without involvement from the brain.
Neurons are the building blocks of the central nervous system. Billions of these nerve cells can be found throughout the body and communicate with one another to produces physical responses and actions.
Neurons are the body's information superhighway. An estimated 86 billion neurons can be found in the brain alone.
Since the CNS is so important, it is protected by a number of structures. First, the entire CNS is enclosed in bone. The brain is protected by the skull, while the spinal cord is protected by the vertebra of the spinal column. The brain and spinal cord are both covered with a protective tissue known as meninges.
The entire CNS is also immersed in a substance known as cerebrospinal fluid, which forms a chemical environment to allow nerve fibers to transmit information effectively as well as offering yet another layer of protection from potential damage.
Volume of distribution
The apparent volume of distribution is the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma. For example, if 1000 mg of a drug is given and the subsequent plasma concentration is 10 mg/L, that 1000 mg seems to be distributed in 100 L (dose/volume = concentration 1000 mg/x L = 10 mg/L therefore, x = 1000 mg/10 mg/L = 100 L).
Volume of distribution has nothing to do with the actual volume of the body or its fluid compartments but rather involves the distribution of the drug within the body. For a drug that is highly tissue-bound, very little drug remains in the circulation thus, plasma concentration is low and volume of distribution is high. Drugs that remain in the circulation tend to have a low volume of distribution.
Volume of distribution provides a reference for the plasma concentration expected for a given dose but provides little information about the specific pattern of distribution. Each drug is uniquely distributed in the body. Some drugs distribute mostly into fat, others remain in extracellular fluid, and others are bound extensively to specific tissues.
Many acidic drugs (eg, warfarin , aspirin ) are highly protein-bound and thus have a small apparent volume of distribution. Many basic drugs (eg, amphetamine , meperidine ) are extensively taken up by tissues and thus have an apparent volume of distribution larger than the volume of the entire body.
What Is a Stimulant?
Stimulants are substances that make people more alert and increase attention and focus by increasing brain function. They also raise the person’s blood pressure, heart rate and breathing rate. In other words, stimulants stimulate the CNS.
Stimulants might only affect a specific organ or organs, such as the heart, lungs, brain or CNS.
Types of Stimulants
Examples of stimulants include epinephrine — used to make the heart beat during cardiac arrest — as well as amphetamine, dextroamphetamine, methylphenidate, cocaine and methamphetamine.
Stimulants such as pseudoephedrine may even be found in some cold medicines.
Prescription stimulants, such as Adderall (a combination of dextroamphetamine and amphetamine) and Ritalin (methylphenidate), are generally used to treat attention-deficit/hyperactivity disorder (ADHD). These drugs are also commonly misused for recreational purposes, increased performance or extreme dieting.
Cocaine is also a local anesthetic, a medication that causes reversible absence of pain sensation. It is the only drug that is classified as both.
Methamphetamine is similar to amphetamine in its chemical composition, but more intense because of its stronger effects. Both drugs are also called psychoactive drugs, or psycho stimulants.
Most stimulants, including cocaine, methamphetamine, methadone, Adderall and Ritalin, are categorized as Schedule II drugs. Schedule II drugs have a high potential for abuse and are considered dangerous. These types of drugs can lead to severe psychological and physical dependence.
Effects of Stimulants
Stimulants act specifically on the brain chemicals dopamine and norepinephrine. The medications increase the activity of these neurotransmitters.
Dopamine and norepinephrine are involved in rewarding behaviors as well as the blood vessels and the regulation of blood pressure, heart rate, blood sugar and breathing, respectively.
After taking stimulants, users feel an initial rush of euphoria. This rush is the pleasurable high that drug abusers seek.
Users will also feel the effects of increased blood pressure, heart rate, breathing and blood sugar levels and decreased blood flow along with the opening of the breathing passages, or easier breathing.
Short-Term Effects of Stimulants Include:
- Intense feelings of happiness or well-being
- Increased energy, social performance and self-esteem
- Improved attention, alertness, awareness or focus
- Increased sexual desire and performance
- Opened airways and easier breathing
- Suppressed appetite
Stimulants are often abused for their euphoric and energizing effects. But these short-term pleasurable feelings can lead to long-term consequences.
People who regularly use stimulants are also at an increased risk of developing a tolerance to the medications. This behavior can lead to dependence and addiction.
Regular misuse of stimulants can cause psychosis, anger or paranoia. Stimulants, when taken at high doses, can also lead to dangerous side effects, such as high body temperature, irregular heartbeat, seizures and heart failure.
Those who use stimulants might experience withdrawal symptoms when they try to stop taking the drug. These symptoms can come on quickly and last for up to several months.
Stimulant Withdrawal Symptoms Include:
- Fatigue or mental and physical exhaustion
- Depression or suicidal thoughts
- Sleep problems
- Irritability, agitation or anxiety
- Intense hunger
- Inability to feel pleasure
Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS et al. Grand challenges in global mental health. Nature 2011 475: 27–30.
Bloom DE, Cafiero E, Jané-Llopis E, Abrahams-Gessel S, Bloom LR, Fathima S et al. The Global Economic Burden of Non-communicable Diseases. Geneva: World Economic Forum 2011.
Miller G . Is pharma running out of brainy ideas. Science 2010 329: 502–504.
Abbott A . Novartis to shut brain research facility. Nature 2011 480: 161–162.
Insel T, Voon V, Nye J, Brown VJ, Altevogt B, Bullmore E et al. Innovative solutions to novel drug development in mental health. Neurosci Biobehav Rev 2013 37: 2438–2444.
Pangalos MN, Schechter LE, Hurko O . Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 2007 6: 521–532.
Hyman SE . Revolution stalled. Sci Transl Med 2012 4: 155cm111–155cm111.
Chong CR, Sullivan DJ . New uses for old drugs. Nature 2007 448: 645–646.
DiMasi JA, Hansen RW, Grabowski HG . The price of innovation: new estimates of drug development costs. J Health Econ 2003 22: 151–185.
Quintana DS, Alvares GA, Hickie IB, Guastella AJ . Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci Biobehav Rev 2015 49: 182–192.
Thorne RG, Pronk GJ, Padmanabhan V, Frey WH II . Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004 127: 481–496.
Thorne RG, Emory CR, Ala TA, Frey WH II . Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res 1995 692: 278–282.
Balin BJ, Broadwell RD, Salcman M, El-Kalliny M . Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J Comp Neurol 1986 251: 260–280.
Djupesland PG, Skretting A, Winderen M, Holand T . Breath actuated device improves delivery to target sites beyond the nasal valve. Laryngoscope 2006 116: 466–472.
Pardridge WM . CNS drug design based on principles of blood-brain barrier transport. J Neurochem 1998 70: 1781–1792.
Yamamoto A, Iseki T, Ochi-Sugiyama M, Okada N, Fujita T, Muranishi S . Absorption of water-soluble compounds with different molecular weights and [Asu 1.7 ]-eel calcitonin from various mucosal administration sites. J Control Release 2001 76: 363–374.
Guastella AJ, Hickie IB, McGuinness MM, Otis M, Woods EA, Disinger HM et al. Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology 2013 38: 612–625.
Miller JL, Ashford JW, Archer SM, Rudy AC, Wermeling DP . Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study. Pharmacotherapy 2008 28: 875–882.
Meredith ME, Salameh TS, Banks WA . Intranasal delivery of proteins and peptides in the treatment of neurodegenerative diseases. AAPS J 2015 17: 780–787.
Miyake MM, Bleier BS . The blood-brain barrier and nasal drug delivery to the central nervous system. Am J Rhinol Allergy 2015 29: 124–127.
Kaminsky BM, Bostwick JR, Guthrie SK . Alternate routes of administration of antidepressant and antipsychotic medications. Ann Pharmacother 2015 49: 808–817.
Jiang Y, Li Y, Liu X . Intranasal delivery: circumventing the iron curtain to treat neurological disorders. Expert Opin Drug Deliv 2015 12: 1717–1725.
Andrade C . Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. J Clin Psychiatry 2015 76: e628–e631.
Flexner S . The mode of infection in epidemic poliomyelitis. J Am Med Assoc 1912 59: 1371–1372.
Clark PF, Fraser FR, Amoss HL . The relation to the blood of the virus of epidemic poliomyelitis. J Exp Med 1914 19: 223–233.
Findlay G, Clarke L . Infection with neurotropic yellow fever virus following instillation into the nares and conjunctival sac. J Pathol Bacteriol 1935 40: 55–64.
Slavin HB, Berry GP . Studies on herpetic infection in mice: II. The pathways of invasion of the central nervous system after intranasal instillation of virus in suckling mice. J Exp Med 1943 78: 315.
Perlman S, Barnett E, Jacobsen G . Mouse hepatitis virus and herpes simplex virus move along different CNS pathways. In: Laude H, Vautherot J-F (eds). Coronaviruses, vol. 342. Springer, New York, 1993, pp 313–318.
Mathison S, Nagilla R, Kompella UB . Nasal route for direct delivery of solutes to the central nervous system: fact or fiction? J Drug Target 1998 5: 415–441.
Sharma S, Mukkur T, Benson HA, Chen Y . Pharmaceutical aspects of intranasal delivery of vaccines using particulate systems. J Pharm Sci 2009 98: 812–843.
Henriksson J, Tallkvist J, Tjälve H . Uptake of nickel into the brain via olfactory neurons in rats. Toxicol Lett 1997 91: 153–162.
Chen X, Fawcett J, Rahman Y, Ala T, Frey I . Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimers Dis 1998 1: 35–44.
Ross T, Martinez P, Renner J, Thorne R, Hanson L, Frey W II . Intranasal administration of interferon beta bypasses the blood–brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol 2004 151: 66–77.
Shipley M . Transport of molecules from nose to brain: transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin-horseradish peroxidase applied to the nasal epithelium. Brain Res Bull 1985 15: 129–142.
Doty RL, Bromley SM . Cranial nerve I: olfactory nerve, chapter 7. In: Goetz CG (ed) Textbook of Clinical Neurology (3rd edn). W.B. Saunders: Philadelphia, 2007 pp 99–112.
Roth G . Sensory systems: the coupling between brain and environment. The Long Evolution of Brains and Minds. Springer, Dordrecht, The Netherlands, 2013, pp 165–192.
Kalogjera L, Dzepina D . Management of smell dysfunction. Curr Allergy Asthma Rep 2012 12: 154–162.
Doty RL . The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 2008 63: 7–15.
Li Y, Field PM, Raisman G . Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres. Glia 2005 52: 245–251.
Kristensson K, Olsson Y . Uptake of exogenous proteins in mouse olfactory cells. Acta Neuropathol (Berl) 1971 19: 145–154.
Dhuria SV, Hanson LR, Frey WH II . Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 2009 99: 1654–1673.
Wolburg H, Wolburg-Buchholz K, Sam H, Horvát S, Deli MA, Mack AF . Epithelial and endothelial barriers in the olfactory region of the nasal cavity of the rat. Histochem Cell Biol 2008 130: 127–140.
Dahlin M, Bergman U, Jansson B, Björk E, Brittebo E . Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res 2000 17: 737–742.
Anand Kumar T, David G, Kumar K, Umberkoman B, Krishnamoorthy M . A new approach to fertility regulation by interfering with neuroendocrine pathways. In: Anand Kumar TC (ed). Neuroendocrine Regulation of Fertility. Karger: Basel, 1976 314–322.
Alcalá-Barraza SR, Lee MS, Hanson LR, McDonald AA, Frey WH, McLoon LK . Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS. J Drug Target 2010 18: 179–190.
Chow HHS, Chen Z, Matsuura GT . Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats. J Pharm Sci 1999 88: 754–758.
Anderson M, Tambe P, Sammons H, Mulla H, Cole R, Choonara I . Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers. Eur J Clin Pharmacol 2012 68: 155–159.
Kumar M, Misra A, Babbar A, Mishra A, Mishra P, Pathak K . Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm 2008 358: 285–291.
Grant I, Nimmo W, Clements J . Pharmacokinetics and analgesic effects of i.m. and oral ketamine. Br J Anaesth 1981 53: 805–810.
Wallum B, Taborsky G Jr, Porte D Jr, Figlewicz D, Jacobson L, Beard J et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 1987 64: 190–194.
Foster K, Roberts M . Experimental methods for studying drug uptake in the head and brain. Curr Drug Metab 2000 1: 333–356.
Hansch C, Clayton JM . Lipophilic character and biological activity of drugs II: the parabolic case. J Pharm Sci 1973 62: 1–21.
Banks WA, Kastin AJ . Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res Bull 1985 15: 287–292.
Smith AL, Freeman SM, Voll RJ, Young LJ, Goodman MM . Investigation of an F-18 oxytocin receptor selective ligand via PET imaging. Bioorg Med Chem Lett 2013 23: 5415–5420.
Smith AL, Freeman SM, Voll RJ, Young LJ, Goodman MM . Carbon-11N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors. Bioorg Med Chem Lett 2013 23: 902–906.
Bartlett JA, van der Voort Maarschalk K . Understanding the oral mucosal absorption and resulting clinical pharmacokinetics of asenapine. AAPS PharmSciTech 2012 13: 1110–1115.
DeSesso JM . The relevance to humans of animal models for inhalation studies of cancer in the nose and upper airways. Qual Assur 1993 2: 213–231.
Frauman AG, Cooper ME, Parsons BJ, Jerums G, Louis WJ . Long-term use of intranasal insulin in insulin-dependent diabetic patients. Diabetes Care 1987 10: 573–578.
Cacciotti-Saija C, Langdon R, Ward PB, Hickie IB, Scott E, Naismith SL et al. A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis. Schizophr Bull 2015 41: 483–493.
Guastella AJ, Gray KM, Rinehart NJ, Alvares GA, Tonge BJ, Hickie IB et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry 2015 56: 444–452.
Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014 76: 970–976.
Carr DB, Goudas LC, Denman WT, Brookoff D, Staats PS, Brennen L et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain 2004 108: 17–27.
Barton ED, Colwell CB, Wolfe T, Fosnocht D, Gravitz C, Bryan T et al. Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med 2005 29: 265–271.
Jansson B, Björk E . Visualization of in vivo olfactory uptake and transfer using fluorescein dextran. J Drug Target 2002 10: 379–386.
Baker H, Spencer RF . Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat. Exp Brain Res 1986 63: 461–473.
Nonaka N, Farr SA, Kageyama H, Shioda S, Banks WA . Delivery of galanin-like peptide to the brain: targeting with intranasal delivery and cyclodextrins. J Pharmacol Exp Ther 2008 325: 513–519.
Danielyan L, Schäfer R, von Ameln-Mayerhofer A, Bernhard F, Verleysdonk S, Buadze M et al. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res 2011 14: 3–16.
Lai M, Topp E . Solid-state chemical stability of proteins and peptides. J Pharm Sci 1999 88: 489–500.
Waterhouse RN . Determination of lipophilicity and its use as a predictor of blood–brain barrier penetration of molecular imaging agents. Mol Imaging Biol 2003 5: 376–389.
Pardridge WM . Drug and gene delivery to the brain: the vascular route. Neuron 2002 36: 555–558.
Adjei A, Sundberg D, Miller J, Chun A . Bioavailability of leuprolide acetate following nasal and inhalation delivery to rats and healthy humans. Pharm Res 1992 9: 244–249.
Proctor DF . The upper airways. I. Nasal physiology and defense of the lungs. Am Rev Respir Dis 1977 115: 97–129.
Weiss L . Cell and Tissue Biology: A Textbook of Histology. Lippincott Williams & Wilkins, 1988.
Schweitzer VG . Osteolytic sinusitis and pneumomediastinum: deceptive otolaryngologic complications of cocaine abuse. Laryngoscope 1986 96: 206–210.
Jones N . The nose and paranasal sinuses physiology and anatomy. Adv Drug Deliv Rev 2001 51: 5–19.
Wexler DB, Davidson TM . The nasal valve: a review of the anatomy, imaging, and physiology. Am J Rhinol 2004 18: 143–150.
Bridger G, Proctor D . Maximum nasal inspiratory flow and nasal resistance. Ann Otol Rhinol Laryngol 1970 79: 481–488.
Aggarwal R, Cardozo A, Homer J . The assessment of topical nasal drug distribution. Clin Otolaryngol Allied Sci 2004 29: 201–205.
Uddströmer M . On the physiology of the nasal respiration. Acta Otolaryngol (Stockh) 1940 28: 15–59.
Mink PJ . Le nez comme voie respiratoire. Presse Otolaryng Belge 1903 2: 481–496.
Mygind N, Dahl R . Anatomy, physiology and function of the nasal cavities in health and disease. Adv Drug Deliv Rev 1998 29: 3–12.
Merkus P, Ebbens FA, Muller B, Fokkens WJ . Influence of anatomy and head position on intranasal drug deposition. Eur Arch Otorhinolaryngol 2006 263: 827–832.
Djupesland PG, Mahmoud RA, Messina JC . Accessing the brain: the nose may know the way. J Cereb Blood Flow Metab 2013 33: 793–794.
Quintana DS, Westlye LT, Rustan ØG, Tesli N, Poppy CL, Smevik H et al. Low dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized 4-way crossover trial with nasal cavity dimension assessment. Transl Psychiatry 2015 5: 1–9.
Sato K, Endo S, Tomita H . Sensitivity of three loci on the tongue and soft palate to four basic tastes in smokers and non-smokers. Acta Otolaryngol (Stockh) 2002 122: 74–82.
Homer J, Raine C . An endoscopic photographic comparison of nasal drug delivery by aqueous spray. Clin Otolaryngol Allied Sci 1998 23: 560–563.
Perez AP, Mundiña-Weilenmann C, Romero EL, Morilla MJ . Increased brain radioactivity by intranasal 32 P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels. Int J Nanomed 2012 7: 1373.
Kanazawa T . Brain delivery of small interfering ribonucleic acid and drugs through intranasal administration with nano-sized polymer micelles. Medl Devices (Auckl) 2015 8: 57.
Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012 69: 29–38.
Hoekman JD, Ho RJ . Enhanced analgesic responses after preferential delivery of morphine and fentanyl to the olfactory epithelium in rats. Anesth Analg 2011 113: 641.
Djupesland PG, Skretting A . Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump. J Aerosol Med Pulm Drug Deliv 2012 25: 280–289.
Blanks AM, Thornton S . The role of oxytocin in parturition. BJOG 2003 110: 46–51.
Fuchs A-R, Fuchs F, Husslein P, Soloff MS, Fernstrom MJ . Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor. Science 1982 215: 1396–1398.
Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry 2007 61: 498–503.
Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 2003 28: 193–198.
Nishimori K, Young LJ, Guo Q, Wang Z, Insel TR, Matzuk MM . Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc Natl Acad Sci USA 1996 93: 11699–11704.
Ruis H, Rolland R, Doesburg W, Broeders G, Corbey R . Oxytocin enhances onset of lactation among mothers delivering prematurely. BMJ 1981 283: 340–342.
McEwen BB . Brain–fluid barriers: relevance for theoretical controversies regarding vasopressin and oxytocin memory research. Adv Pharmacol 2004 50: 531–592.
Fisher A, Brown K, Davis S, Parr G, Smith D . The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat. J Pharm Pharmacol 1987 39: 357–362.
Neumann ID, Landgraf R . Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 2012 35: 649–659.
Neumann ID, Maloumby R, Beiderbeck DI, Lukas M, Landgraf R . Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology 2013 38: 1985–1993.
Striepens N, Kendrick KM, Hanking V, Landgraf R, Wüllner U, Maier W et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep 2013 3: 3440.
Nelson E, Panksepp J . Oxytocin mediates acquisition of maternally associated odor preferences in preweanling rat pups. Behav Neurosci 1996 110: 583.
Popik P, Vetulani J, Van Ree JM . Low doses of oxytocin facilitate social recognition in rats. Psychopharmacology (Berl) 1992 106: 71–74.
Eckstein M, Becker B, Scheele D, Scholz C, Preckel K, Schlaepfer TE et al. Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 2014 78: 194–202.
Groppe SE, Gossen A, Rademacher L, Hahn A, Westphal L, Gründer G et al. Oxytocin influences processing of socially relevant cues in the ventral tegmental area of the human brain. Biol Psychiatry 2013 74: 172–179.
Striepens N, Scheele D, Kendrick KM, Becker B, Schäfer L, Schwalba K et al. Oxytocin facilitates protective responses to aversive social stimuli in males. Proc Natl Acad Sci USA 2012 109: 18144–18149.
Dadds MR, MacDonald E, Cauchi A, Williams K, Levy F, Brennan J . Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord 2014 44: 521–531.
Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010 67: 692–694.
Anagnostou E, Soorya L, Chaplin W, Bartz J, Halpern D, Wasserman S et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 2012 3: 16.
Andari E, Duhamel J-R, Zalla T, Herbrecht E, Leboyer M, Sirigu A . Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 2010 107: 4389–4394.
Fang A, Hoge EA, Heinrichs M, Hofmann SG . Attachment style moderates the effects of oxytocin on social behaviors and cognitions during social rejection applying a research domain criteria framework to social anxiety. Clin Psychol Sci 2014 2: 740–747.
Guastella AJ, Ward PB, Hickie IB, Shahrestani S, Hodge MAR, Scott EM et al. A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia. Schizophr Res 2015.
Lee MR, Wehring HJ, McMahon RP, Linthicum J, Cascella N, Liu F et al. Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: results from a randomized double blind placebo controlled pilot study. Schizophr Res 2013 145: 110–115.
Davis MC, Lee J, Horan WP, Clarke AD, McGee MR, Green MF et al. Effects of single dose intranasal oxytocin on social cognition in schizophrenia. Schizophr Res 2013 147: 393–397.
McRae-Clark AL, Baker NL, Moran-Santa Maria M, Brady KT . Effect of oxytocin on craving and stress response in marijuana-dependent individuals: a pilot study. Psychopharmacology (Berl) 2013 228: 623–631.
MacDonald K, MacDonald TM, Brüne M, Lamb K, Wilson MP, Golshan S et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinology 2013 38: 2831–2843.
Muin DA, Wolzt M, Marculescu R, Rezaei SS, Salama M, Fuchs C et al. Effect of long-term intranasal oxytocin on sexual dysfunction in premenopausal and postmenopausal women: a randomized trial. Fertil Steril 2015 104: 715–723.
Einfeld SL, Smith E, McGregor IS, Steinbeck K, Taffe J, Rice LJ et al. A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome. Am J Med Genet A 2014 164: 2232–2239.
Cacciotti-Saija C, Langdon R, Ward PB, Hickie IB, Scott EM, Naismith SL et al. A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis. Schizophr Bull 2014 41: 483–493.
Bakermans-Kranenburg M, Van Ijzendoorn M . Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl Psychiatry 2013 3: e258.
Wigton R, Jocham Radua PA, Averbeck B, Meyer-Lindenberg A, McGuire P, Shergill SS et al. Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. J Psychiatry Neurosci 2015 40: E1.
Adolphs R . The neurobiology of social cognition. Curr Opin Neurobiol 2001 11: 231–239.
Rilling JK, DeMarco AC, Hackett PD, Thompson R, Ditzen B, Patel R et al. Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 2012 37: 447–461.
Paloyelis Y, Doyle OM, Zelaya FO, Maltezos S, Williams SC, Fotopoulou A et al. A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol Psychiatry 2014.
Boccia ML, Petrusz P, Suzuki K, Marson L, Pedersen CA . Immunohistochemical localization of oxytocin receptors in human brain. Neuroscience 2013 253: 155–164.
Dal Monte O, Noble PL, Turchi J, Cummins A, Averbeck BB . CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One 2014 9: e103677.
Chang SW, Barter JW, Ebitz RB, Watson KK, Platt ML . Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc Natl Acad Sci USA 2012 109: 959–964.
Kendrick K, Keverne E, Hinton M, Goode J . Cerebrospinal fluid and plasma concentrations of oxytocin and vasopressin during parturition and vaginocervical stimulation in the sheep. Brain Res Bull 1991 26: 803–807.
Leng G, Ludwig M . Intranasal oxytocin: myths and delusions. Biol Psychiatry 2015.
Quintana DS, Woolley JD . Intranasal oxytocin mechanisms can be better understood but its effects on social cognition and behavior are not to be sniffed at. Biol Psychiatry 2015 in press.
Goldman RD . Intranasal drug delivery for children with acute illness. Curr Drug Ther 2006 1: 127–130.
Howes M . Ketamine for paediatric sedation/analgesia in the emergency department. Emerg Med J 2004 21: 275.
Barceloux DG . KetamineMedical Toxicology of Drug Abuse. John Wiley & Sons, Inc, 2012 pp 110–119.
Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos 2003 24: 37–43.
Malinovsky J, Servin F, Cozian A, Lepage J, Pinaud M . Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 1996 77: 203–207.
Sanacora G, Treccani G, Popoli M . Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 2012 62: 63–77.
Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2014 170: 1134–1142.
Horacek J, Brunovsky M, Novak T, Tislerova B, Palenicek T, Bubenikova-Valesova V et al. Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect. Psychol Med 2010 40: 1443–1451.
Zarate CA Jr, Brutsche N, Laje G, Luckenbaugh DA, Venkata SLV, Ramamoorthy A et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry 2012 72: 331–338.
Kaube H, Herzog J, Käufer T, Dichgans M, Diener H . Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000 55: 139–141.
Wolfe T, Barton E . Nasal drug delivery in EMS: reducing needlestick risk. JEMS 2003 28: 52–63.
Barton ED, Ramos J, Colwell C, Benson J, Baily J, Dunn W . Intranasal administration of naloxone by paramedics. Prehosp Emerg Care 2002 6: 54–58.
Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013 382: 951–962.
Modi ME, Connor-Stroud F, Landgraf R, Young LJ, Parr LA . Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 2014 45: 49–57.
Bethlehem RAI, van Honk J, Auyeung B, Baron-Cohen S . Oxytocin, brain physiology, and functional connectivity: a review of intranasal oxytocin fMRI studies. Psychoneuroendocrinology 2013 38: 962–974.
Quintana DS, Kemp AH, Alvares GA, Guastella AJ . A role for autonomic cardiac control in the effects of oxytocin on social behavior and psychiatric illness. Front Neurosci 2013 7: 48.
Dadds MR, MacDonald E, Cauchi A, Williams K, Levy F, Brennan J . Nasal oxytocin for social deficits in childhood autism: A randomized controlled trial. J Autism Dev Disord 2014 44: 521–531.
Eckstein M, Becker B, Scheele D, Scholz C, Preckel K, Schlaepfer TE et al. Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 2014 78: 194–202.
Guastella AJ, Mitchell PB, Mathews F . Oxytocin enhances the encoding of positive social memories in humans. Biol Psychiatry 2008 64: 256–258.
Guastella AJ, Howard AL, Dadds MR, Mitchell P, Carson DS . A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology 2009 34: 917–923.
McIntyre RS, Soczynska JK, Woldeyohannes HO, Miranda A, Vaccarino A, MacQueen G et al. A randomized, double‐blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord 2012 14: 697–706.