Insufflation (medicine)

 

For other uses, see Insufflation (disambiguation).

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Insufflation (Latin insufflatio "blowing on" or "into") is the practice of inhaling a substance.[1] Insufflation has limited medical use, but is a common route of administration with many respiratory drugs used to treat conditions in the lungs (asthma oremphysema) and paranasal sinus (allergy).

The technique is common for many recreational drugs and is also used for some entheogens. Nasal insufflation (snorting) is commonly used for many psychoactive drugs because it causes a much faster onset than orally and bioavailability is usually, but not always, higher than orally. This bioavailability occurs due to the quick absorption of molecules into the bloodstream through the soft tissue in the mucous membrane of the sinus cavity. Some drugs have a higher rate of absorption, and are thus more effective in smaller doses, through this route.

The intranasal route (administration through the nose) may allow certain drugs and other molecules to bypass the blood-brain barrier via diffusion or axonal transport along olfactory and trigeminal nerves.[2]

Medical uses

Medical procedure

Inert, nontoxic gases, such as carbon dioxide, are often insufflated into a body cavity, in order to expand workroom, or reduce obstruction during minimally invasive or laparoscopic surgery.

In the 18th century, the tobacco smoke enema, an insufflation of tobacco smoke into the rectum, was a common method of reviving drowning victims. [3]

Intranasal (IN) administration of various lipid soluble medications is increasing in popularity. It is often used for treatment of paediatric patients or patients who are otherwise alarmed or frightened by needles, or where Intravenous (IV) access is unavailable. In addition to a variety of Nasal sprays readily available from pharmacies, some common medications delivered via IN include Fentanyl, Midazolam and Naloxone. The time of onset for drugs delivered intranasally is generally only marginally slower than if given via IV.

Administering drugs

Psychoactive substances are often insufflated nasally for the purpose of intranasal absorption through the mucous membrane, which is often more rapid, or more complete, than gastrointestinal absorption. For a substance to be effective when insufflated, it must be water soluble so it can be absorbed into the mucous membranes. This practice is commonly referred to as snorting, bumping, railing, or doozing[4].

Although the majority of a dose of insufflated drug is taken up through the mucous membranes, some enters other parts of the gastrointestinal tract where it may also be absorbed. This is because some of the dose drips down the throat and into the stomach. This effect is commonly referred to as the ‘drip’ and is often unpleasant to taste.

Commonly insufflated psychoactive substances (for non-medical use) include:

  • Cocaine (benzoylmethylecgonine) – a strong stimulant that is highly addictive; most commonly associated with drug insufflation
  • Opioids – a class of analgesic drugs (including heroin, morphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, and the synthetic meperidine and fentanyl).
  • Amphetamines – another class of strong stimulants (including amphetamine, dextroamphetamine and methamphetamine) that are also highly addictive.
  • Ritalin (methylphenidate) – another stimulant closely related to amphetamine, but often reported to have effects similar to that of cocaine when insufflated
  • Ketamine – a dissociative anesthetic, used recreationally for its euphoric, anesthetic, and hallucinatory effects
  • Phencyclidine – a dissociative anesthetic, commonly known as PCP or angel dust; no longer in common use because of reports of intensely negative experiences
  • MDMA/Ecstasy – an entactogen that also possesses stimulant effects
  • Zolpidem (Ambien) – a sedative hypnotic that can have various hallucinogenic effects with certain people and/or at high doses
  • Tobacco snuff – contains nicotine, a mild stimulant that is highly addictive.

Various other drugs can be taken in intranasally for research purposes such as the neuropeptides MSH/ACTH, vasopressin and insulin.[5]

Note: Some psychoactive substances such as benzodiazepines (valium, oxazepam, clonazepam) are water soluble to a small degree (about 350ml/1000 mg). Though this means they will be somewhat effective when insufflated, they will not be as readily absorbed into the mucous membrane as highly soluble substances such as amphetamines and opiates. Typically sublingual administration is preferred for this class of drugs.

Dangers

Many recreational drugs which are commonly insufflated such as cocaine, can cause damage to the nasal cavity and has even been known to destroy the nasal septum[6]. Any damage to the inside of the nose is either because some insufflation highly constricts blood vessels – and therefore blood and oxygen/nutrient flow – to that area, or because the substance is physically caustic. A famous case where the septum was completely destroyed by cocaine was of Eastenders star Danniella Westbrook.

References

  1. ^ http://www.merriam-webster.com/medical/insufflation
  2. ^ William H. Frey. "Bypassing the Blood-Brain Barrier to Deliver Therapeutic Agents to the Brain and Spinal Cord." Drug Delivery Technology.
  3. ^ Lawrence, Ghislaine (20 April 2002). "Tobacco smoke enemas". The Lancet 359 (9315): 1442. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08339-3/fulltext. Retrieved 2008-11-27.
  4. ^ Definition of dooze, definition #4 ["http://www.urbandictionary.com/define.php?term=dooze"]
  5. ^ Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. (2002). Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci.5(6):514-6. doi:10.1038/nn849 PMID 11992114
  6. ^ http://www.thesite.org/drinkanddrugs/drugsafety/drugsandyourbody/cokeandyournose

vde

Routes of administration / Dosage forms

Oral

Digestive tract (enteral)

Solids

Pill · Tablet · Capsule · Osmotic controlled release capsule (OROS) · Softgel

Liquids

Solution · Suspension · Emulsion · Syrup · Elixir · Tincture · Hydrogel

Buccal / Sublabial / Sublingual

Solids

Orally Disintegrating Tablet (ODT) · Film · Lollipop · Lozenges · Chewing gum

Liquids

Mouthwash · Toothpaste · Ointment · Oral spray

Respiratory tract

Solids

Smoking device · Dry Powder Inhaler (DPI)

Liquids

pressurized Metered Dose Inhaler (pMDI) · Nebulizer · Vaporizer

Gas

Oxygen mask · Oxygen concentrator · Anaesthetic machine · Relative analgesia machine

FlattenedRoundPills.jpg
Hexaaquatitanium(III)-solution.jpg
Inhaler.jpg
Glycerin suppositories.jpg
SPF15SunBlock.JPG
Syringe2.jpg
Questionmark.png

Ocular / Otologic / Nasal

Nasal spray · Ear drops · Eye drops · Ointment · Hydrogel · Nanosphere suspension · Mucoadhesive microdisc (microsphere tablet)

Urogenital

Ointment · Pessary (vaginal suppository) · Vaginal ring · Vaginal douche · Intrauterine device (IUD) · Extra-amniotic infusion · Intravesical infusion

Rectal (enteral)

Ointment · Suppository · Enema (Solution · Hydrogel) · Murphy drip

Dermal

Ointment · Liniment · Paste · Film · Hydrogel · Liposomes · Transfersome vesicals · Cream · Lotion · Lip balm · Medicated shampoo · Dermal patch · Transdermal patch · Transdermal spray · Jet injector

Injection / Infusion
(into tissue/blood)

Skin

Intradermal · Subcutaneous · Transdermal implant

Organs

Intracavernous · Intravitreal · Transscleral

Central nervous system

Intracerebral · Intrathecal · Epidural

Circulatory / Musculoskeletal

Intravenous · Intracardiac · Intramuscular · Intraosseous · Intraperitoneal · Nanocell injection

Additional explanation:

Mucous membranes are used by the human body to absorb the dosage for all routes of administration, except for "Dermal" and "Injection/Infusion".
Administration routes can also be grouped as Topical (local effect) or Systemic (defined as Enteral = Digestive tract/Rectal, or Parenteral = All other routes).

 

vde

Routes of administration

Gastrointestinal

Oral · Buccal · Sublabial · Sublingual · Rectal

Respiratory system

Pulmonary · Nasal

Visual system / Auditory system

Ocular (Ocular-topical / Intravitreal / Transscleral) · Otologic (Oto-topical)

Reproductive system

Intracavernous · Intravaginal · Intrauterine (Extra-amniotic)

Urinary system

Intravesical

Peritoneum

Intraperitoneal

Central nervous system

Intracerebral · Intrathecal · Epidural

Circulatory system

Intravenous · Intracardiac

Musculoskeletal system

Intramuscular · Intraosseous

Skin

Epicutaneous · Intradermal · Subcutaneous

 

Blood-brain barrier

 

Part of a network of capillaries supplying brain cells

The blood-brain barrier (BBB) is a separation of circulating blood and cerebrospinal fluid (CSF) in the central nervous system (CNS). It occurs along all capillaries and consists of tight junctions around the capillaries that don’t exist in normal circulation. Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria) and large or hydrophilic molecules into the CSF, while allowing the diffusion of smallhydrophobic molecules (O2, hormones, CO2). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins.

Physiology

This "barrier" results from the selectivity of the tight junctions between endothelial cells in CNS vessels that restricts the passage of solutes. At the interface between blood and the brain, endothelial cells are stitched together by these tight junctions, which are composed of smaller subunits, frequently biochemical dimers, that are transmembrane proteins such as occludin, claudins, junctional adhesion molecule (JAM), or ESAM, for example. Each of these transmembrane proteins is anchored into the endothelial cells by another protein complex that includes zo-1 and associated proteins.

The blood-brain barrier is composed of high-density cells restricting passage of substances from the bloodstream much more than endothelial cells in capillaries elsewhere in the body. Astrocyte cell projections called astrocytic feet (also known as "glia limitans") surround the endothelial cells of the BBB, providing biochemical support to those cells. The BBB is distinct from the quite similar blood-cerebrospinal fluid barrier, which is a function of the choroidal cells of the choroid plexus, and from the blood-retinal barrier, which can be considered a part of the whole realm of such barriers.[1]

Several areas of the human brain are not "behind" the BBB. These include the circumventricular organs. One example of this is the pineal gland, which secretes the hormone melatonin "directly into the systemic circulation"[2] as this hormone can pass through the blood-brain barrier.[3]

History

Paul Ehrlich was a bacteriologist studying staining, a procedure that is used in many microscopic studies to make fine biological structures visible. When Ehrlich injected some of these dyes (notably the aniline dyes that were then widely-used), the dye would stain all of the organs of some kinds of animals except for their brains. At that time, Ehrlich attributed this lacking to the brain’s simply not picking up as much of the dye.

However, in a later experiment in 1913, Edwin Goldmann (one of Ehrlich’s students) injected the dye into the cerebro-spinal fluids of animal’s brains directly. He found that in this case the brains did become dyed, but the rest of the body did not. This clearly demonstrated the existence of some sort of compartmentalization between the two. At that time, it was thought that the blood vessels themselves were responsible for the barrier, since no obvious membrane could be found. The concept of the blood-brain barrier (then termed hematoencephalic barrier) was proposed by Lina Stern in 1921.[4] It was not until the introduction of the scanning electron microscope to the medical research fields in the 1960s that the actual membrane could be observed and proven to exist.

Pathophysiology

The blood-brain barrier acts very effectively to protect the brain from many common bacterial infections. Thus, infections of the brain are very rare. However, since antibodies and antibiotics are too large to cross the blood-brain barrier, infections of the brain that do occur are often very serious and difficult to treat. However, the blood-brain barrier becomes more permeable during inflammation, meaning that some antibiotics can get across. Viruses easily bypass the blood-brain barrier by attaching themselves to circulating immune cells.

An exception to the bacterial exclusion are the diseases caused by spirochetes, such as Borrelia, which causes Lyme disease, and Treponema pallidum, which causes syphilis. These harmful bacteria seem to breach the blood-barrier by physically tunneling through the blood vessel walls.

There are also some biochemical poisons that are made up of large molecules that are too big to pass through the blood-brain barrier. This was especially important in primitive or medieval times when people often ate contaminated food. Neurotoxins such as Botulinum in the food might affect peripheral nerves, but the blood-brain barrier can often prevent such toxins from reaching the central nervous system, where they could cause serious or fatal damage.

Drugs targeting the brain

Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. In its neuroprotective role, the blood-brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts.

Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for drug delivery through the BBB entail its disruption by osmotic means; biochemically by the use of vasoactive substances such as bradykinin; or even by localized exposure to high-intensity focused ultrasound (HIFU). Other methods used to get through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters such as glucose and amino acid carriers; receptor-mediated transcytosis for insulin or transferrin; and the blocking of active efflux transporters such as p-glycoprotein. Methods for drug delivery behind the BBB include intracerebral implantation (such as with needles) and convection-enhanced distribution. Mannitol can be used in bypassing the BBB.

Nanoparticles

Nanotechnology may also help in the transfer of drugs across the BBB.[5] Recently, researchers have been trying to build liposomes loaded with nanoparticles to gain access through the BBB. More research is needed to determine which strategies will be most effective and how they can be improved for patients with brain tumors. The potential for using BBB opening to target specific agents to brain tumors has just begun to be explored.

Delivering drugs across the blood-brain barrier is one of the most promising applications of nanotechnology in clinical neuroscience. Nanoparticles could potentially carry out multiple tasks in a predefined sequence, which is very important in the delivery of drugs across the blood-brain barrier.

A significant amount of research in this area has been spent exploring methods of nanoparticle-mediated delivery of antineoplastic drugs to tumors in the central nervous system. For example, radiolabeled polyethylene glycol coated hexadecylcyanoacrylate nanospheres targeted and accumulated in a rat gliosarcoma.[6] However, this method is not yet ready for clinical trials, due to the accumulation of the nanospheres in surrounding healthy tissue.

It should be noted that vascular endothelial cells and associated pericytes are often abnormal in tumors and that the blood-brain barrier may not always be intact in brain tumors. Also, the basement membrane is sometimes incomplete. Other factors, such as astrocytes, may contribute to the resistance of brain tumors to therapy.[7][8]

Diseases involving the blood-brain barrier

Meningitis

Meningitis is an inflammation of the membranes that surround the brain and spinal cord (these membranes are known as meninges). Meningitis is most commonly caused by infections with various pathogens, examples of which are Streptococcus pneumoniae and Haemophilus influenzae. When the meninges are inflamed, the blood-brain barrier may be disrupted. This disruption may increase the penetration of various substances (including either toxins or antibiotics) into the brain. Antibiotics used to treat meningitis may aggravate the inflammatory response of the central nervous system by releasing neurotoxins from the cell walls of bacteria-like lipopolysaccharide (LPS) [9] Treatment with third-generation or fourth-generation cephalosporin is usually preferred.

Epilepsy

Epilepsy is a common neurological disease that is characterized by recurrent and sometimes untreatable seizures. Several clinical and experimental data have implicated the failure of blood-brain barrier function in triggering chronic or acute seizures,[10][11]some studies implicate the interactions between a common blood protein – albumin and astrocytes.[12] These findings have shown that acute seizures are a predictable consequence of disruption of the BBB by either artificial or inflammatory mechanisms. In addition, expression of drug resistance molecules and transporters at the BBB are a significant mechanism of resistance to commonly used anti-epileptic drugs.[13]

Multiple sclerosis (MS)

Multiple sclerosis (MS) is considered to be an auto-immune and neurodegenerative disorder in which the immune system attacks the myelin that protects and electrically insulates the neurons of the central and peripheral nervous systems. Normally, a person’s nervous system would be inaccessible to the white blood cells due to the blood-brain barrier. However, it has been shown using Magnetic Resonance Imaging, that when a person is undergoing an MS "attack," the blood-brain barrier has broken down in a section of the brain or spinal cord, allowing white blood cells called T lymphocytes to cross over and attack the myelin. It has sometimes been suggested that, rather than being a disease of the immune system, MS is a disease of the blood-brain barrier.[14] A recent study suggests that the weakening of the blood-brain barrier is a result of a disturbance in the endothelial cells on the inside of the blood vessel, due to which the production of the protein P-glycoprotein is not working well.

There are currently active investigations into treatments for a compromised blood-brain barrier. It is believed that oxidative stress plays an important role into the breakdown of the barrier. Anti-oxidants such as lipoic acid may be able to stabilize a weakening blood-brain barrier.[15]

Neuromyelitis optica

Neuromyelitis optica, also known as Devic’s disease, is similar to and is often confused with multiple sclerosis. Among other differences from MS, a different target of the autoimmune response has been identified. Patients with neuromyelitis optica have high levels of antibodies against a protein called aquaporin 4 (a component of the astrocytic foot processes in the blood-brain barrier).[16]

Late-stage neurological trypanosomiasis (Sleeping sickness)

Late-stage neurological trypanosomiasis, or sleeping sickness, is a condition in which trypanosoma protozoa are found in brain tissue. It is not yet known how the parasites infect the brain from the blood, but it is suspected that they cross through thechoroid plexus, a circumventricular organ.

Progressive multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is caused by reactivation of a latent papovavirus (the JC polyomavirus) infection, that can cross the BBB. It affects immune-compromised patients and it is usually seen with patients suffering from AIDS.

De Vivo disease

De Vivo disease (also known as GLUT1 deficiency syndrome) is a rare condition caused by inadequate transportation of the sugar, glucose, across the blood-brain barrier, resulting in mental retardation and other neurological problems. Genetic defects inglucose transporter type 1 (GLUT1) appears to be the primary cause of De Vivo disease.[17][18]

Alzheimer’s Disease

Some new evidence indicates [19] that disruption of the blood-brain barrier in Alzheimer’s Disease patients allows blood plasma containing amyloid beta (Aβ) to enter the brain where the Aβ adheres preferentially to the surface of astrocytes. These findings have led to the hypotheses that (1) breakdown of the blood-brain barrier allows access of neuron-binding autoantibodies and soluble exogenous Aβ42 to brain neurons and (2) binding of these auto-antibodies to neurons triggers and/or facilitates the internalization and accumulation of cell surface-bound Aβ42 in vulnerable neurons through their natural tendency to clear surface-bound autoantibodies via endocytosis. Eventually the astrocyte is overwhelmed, dies, ruptures, and disintegrates, leaving behind the insoluble Aβ42 plaque. Thus, in some patients, Alzheimer’s disease may be caused (or more likely, aggravated) by a breakdown in the blood-brain barrier. [1]

The herpes virus produces the amyloid beta (Aβ), and this virus has been found to be the pathogen responsible for being a major cause of the disease. [2]

HIV Encephalitis

It is believed [20] that latent HIV can cross the blood-brain barrier inside circulating monocytes in the bloodstream ("Trojan horse theory") within the first 14 days of infection. Once inside, these monocytes become activated and are transformed into macrophages. Activated macrophages release virions into the brain tissue proximate to brain microvessels. These viral particles likely attract the attention of sentinel brain microglia and perivascular macrophages initiating an inflammatory cascade that may cause a series of intracellular signaling in brain microvascular endothelial cells and damage the functional and structural integrity of the BBB. This inflammation is HIV encephalitis (HIVE). Instances of HIVE probably occur throughout the course of AIDS and are a precursor for HIV-associated dementia (HAD). The premier model for studying HIV and HIVE is the simian model.

References

  1. ^ Hamilton RD, Foss AJ, Leach L (2007). "Establishment of a human in vitro model of the outer blood-retinal barrier". Journal of Anatomy 211: 707. doi:10.1111/j.1469-7580.2007.00812.x. PMID 17922819.
  2. ^ Pritchard, Thomas C.; Alloway, Kevin Douglas (1999) (Google books preview). Medical Neuroscience. Hayes Barton Press. pp. 76–77. ISBN 1889325295. Retrieved 2009-02-08.
  3. ^ Gilgun-Sherki, Yossi; Melamed, Eldad and Offen, Daniel.(2001). Neuropharmacology. Volume 40, Issue 8, June 2001, Pages 959-975. doi:10.1016/S0028-3908(01)00019-3
  4. ^ Lina Stern: Science and fate by A.A. Vein. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
  5. ^ Silva, GA (December 2008). "Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS". BMC Neuroscience 9 (Suppl. 3): S4. doi:10.1186/1471-2202-9-S3-S4. PMID 19091001.
  6. ^ Brigger I, Morizet J, Aubert G, et al. (December 2002). "Poly(ethylene glycol)-coated hexadecylcyanoacrylate nanospheres display a combined effect for brain tumor targeting". J. Pharmacol. Exp. Ther. 303 (3): 928–36. doi:10.1124/jpet.102.039669.PMID 12438511.
  7. ^ Hashizume, H; Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (April 2000). "Openings between defective endothelial cells explain tumor vessel leakiness". American Journal of Pathology 156 (4): 1363–1380.PMID 10751361.
  8. ^ Schneider, SW; Ludwig T, Tatenhorst L, Braune S, Oberleithner H, Senner V, Paulus W (March 2004). "Glioblastoma cells release factors that disrupt blood-brain barrier features". Acta Neuropathologica 107 (3): 272–276. doi:10.1007/s00401-003-0810-2.PMID 14730455.
  9. ^ Beam, TR Jr.; Allen, JC (December 1977). "Blood, brain, and cerebrospinal fluid concentrations of several antibiotics in rabbits with intact and inflamed meninges". Antimicrobial agents and chemotherapy 12 (6): 710–6. PMID 931369.
  10. ^ E. Oby and D. Janigro, The Blood-brain barrier and epilepsy. Epilepsia. 2006 Nov;47(11):1761-74
  11. ^ Marchi,N. et al. Seizure-Promoting Effect of Blood-Brain Barrier Disruption. Epilepsia 48(4), 732-742 (2007). Seiffert,E. et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J. Neurosci. 24, 7829-7836 (2004). Uva,L. et al. Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood-brain barrier permeability. Neuroscience (2007). van Vliet,E.A. et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130, 521-534 (2007).
  12. ^ Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O et al. (2007). "TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis.". Brain 130 (Pt 2): 535–47. doi:10.1093/brain/awl317. PMID 17121744.
  13. ^ Awasthi,S. et al. RLIP76, a non-ABC transporter, and drug resistance in epilepsy. BMC. Neurosci. 6, 61 (2005). Loscher,W. & Potschka,H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat. Rev. Neurosci. 6, 591-602 (2005).
  14. ^ Waubant E (2006). "Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis". Disease Markers 22 (4): 235–44. PMID 17124345.
  15. ^ Schreibelt G, Musters RJ, Reijerkerk A, et al. (August 2006). "Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity". J. Immunol. 177 (4): 2630–7. PMID 16888025.
  16. ^ Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (August 2005). "IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel". J. Exp. Med. 202 (4): 473–7. doi:10.1084/jem.20050304. PMID 16087714.
  17. ^ Pascual, JM; Wang D, Lecumberri B, Yang H, Mao X, Yang R, De Vivo DC (May 2004). "GLUT1 deficiency and other glucose transporter diseases". European journal of endocrinology 150 (5): 627–33. doi:10.1530/eje.0.1500627. PMID 15132717.
  18. ^ Klepper, J; Voit T (June 2002). "Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain– a review". European journal of pediatrics 161 (6): 295–304. doi:10.1007/s00431-002-0939-3. PMID 12029447.
  19. ^ Microvascular injury and blood–brain barrier leakage in Alzheimer’s disease – Zipser et al 2006
  20. ^ http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.neuro.25.112701.142822?cookieSet=1
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