Intranasal absorption features low lipophilicity, enzymatic degradation within the nasal cavity, large molecular size, and rapid mucociliary clearance from the nasal passages, which explains the low  risk of systemic exposure of the administered drug absorbed  via intranasal. [ 33 ]


By delivering drugs almost directly to the site of action, the risk of systemic  side effects  is reduced. [ 25 ]


Skin absorption (dermal absorption), for example, is to directly deliver drug to the skin and, hopefully, to the systemic circulation. [ 34 ]  However, skin irritation may result, and for some forms such as creams or lotions, the dosage is difficult to control. [ 26 ]  Upon contact with the skin, the drug penetrates into the dead  stratum corneum  and can afterwards reach the viable  epidermis , the  dermis , and the  blood vessels . [ 34 ]


The term parenteral is from para-1 'beside' + Greek enteron 'intestine' + -al. This name is due to the fact that it encompasses a route of administration that is not intestinal. However, in common English the term has mostly been used to describe the four most well-known routes of injection.


The term injection encompasses  intravenous  (IV),  intramuscular  (IM),  subcutaneous  (SC) and  intradermal  (ID) administration. [ 35 ]


Parenteral administration generally acts more rapidly than topical or enteral administration, with onset of action often occurring in 15–30 seconds for IV, 10–20 minutes for IM and 15–30 minutes for SC. [ 36 ]  They also have essentially 100%  bioavailability  and can be used for drugs that are poorly absorbed or ineffective when they are given orally. [ 25 ]  Some medications, such as certain  antipsychotics , can be administered as  long-acting intramuscular injections . [ 37 ]  Ongoing  IV infusions  can be used to deliver continuous medication or  fluids . [ 38 ]


Disadvantages of injections include potential pain or discomfort for the patient and the requirement of trained staff using  aseptic techniques  for administration. [ 25 ]  However, in some cases, patients are taught to self-inject, such as SC injection of insulin in patients with  insulin-dependent diabetes mellitus . As the drug is delivered to the site of action extremely rapidly with IV injection, there is a risk of  overdose  if the dose has been calculated incorrectly, and there is an increased risk of side effects if the drug is administered too rapidly. [ 25 ]


Inhaled medications can be absorbed quickly and act both locally and systemically. [ 26 ]  Proper technique with  inhaler  devices is necessary to achieve the correct dose. Some medications can have an unpleasant taste or irritate the mouth. [ 26 ]


In general, only 20–50% of the pulmonary-delivered dose rendered in powdery particles will be deposited in the lung upon mouth inhalation. [ 47 ]  The remainder of 50-70% undeposited aerosolized particles are cleared out of lung as soon as  exhalation . [ 47 ]


An inhaled powdery particle that is >8 μm is structurally predisposed to depositing in the central and conducting airways ( conducting zone ) by inertial impaction. [ 47 ]


An inhaled powdery particle that is between 3 and 8 μm in diameter tend to largely deposit in the  transitional zones  of the lung by sedimentation. [ 47 ]


An inhaled powdery particle that is <3 μm in diameter is structurally predisposed to depositing primarily in the  respiratory regions  of the peripheral lung via diffusion. [ 47 ]


Particles that deposit in the upper and central airways are generally absorbed systemically to great extent because they are only partially removed by  mucociliary  clearance, which results in orally mediated absorption when the transported mucus is swallowed, and first pass metabolism or incomplete absorption through loss at the fecal route can sometimes reduce the bioavailability. [ 48 ]  This should in no way suggest to clinicians or researchers that inhaled particles are not a greater threat than swallowed particles, it merely signifies that a combination of both methods may occur with some particles, no matter the size of or lipo/hydrophilicity of the different particle surfaces. [ 47 ]


Inhalation by nose of a substance is almost identical to oral inhalation, except that some of the drug is absorbed intranasally instead of in the oral cavity before entering the airways. Both methods can result in varying levels of the substance to be deposited in their respective initial cavities, and the level of mucus in either of these cavities will reflect the amount of substance swallowed. The rate of inhalation will usually determine the amount of the substance which enters the lungs. Faster inhalation results in more rapid absorption because more substance finds the lungs. Substances in a form that resists absorption in the lung will likely resist absorption in the nasal passage, and the oral cavity, and are often even more resistant to absorption after they fail absorption in the former cavities and are swallowed.


Neural drug delivery is the next step beyond the basic addition of  growth factors  to  nerve guidance conduits .  Drug delivery systems  allow the rate of growth factor release to be regulated over time, which is critical for creating an environment more closely representative of in vivo development environments. [ 49 ]


In medicine, a  bolus  (from  Latin   bolus , ball) is the administration of a discrete amount of  medication ,  drug , or other compound within a specific time, generally 1–30 minutes, [ 1 ]  to raise its concentration in  blood  to an  effective level . The administration can be given by  injection :  intravenously ,  intramuscularly ,  intrathecally ,  subcutaneously , or by  inhalation . [ clarification needed ]  The article on  routes of administration  provides more information, as the preceding list of ROAs is not exhaustive.


The placement of the bolus dose depends on the systemic levels of the contents desired throughout the body. An intramuscular injection of  vaccines  allows for a slow release of the antigen to stimulate the body's  immune system  and to allow time for developing  antibodies . Subcutaneous injections are used by  heroin  addicts (called 'skin popping', referring to the bump formed by the bolus of heroin), to sustain a slow release that staves off  withdrawal  symptoms without producing  euphoria . [ 2 ]


A bolus delivered directly to the veins through an  intravenous drip  allows a much faster delivery which quickly raises the concentration of the substance in the blood to an effective level. This is typically done at the beginning of a treatment or after a removal of medicine from blood (e.g. through  dialysis ).


Diabetics  and health care professionals use bolus to refer to a dosage of fast-acting  insulin  with a meal (as opposed to  basal rate , which is a dose of slow-acting insulin or the continuous pumping of a small quantity of fast-acting insulin to cover the  glucose  output of the  liver ). [ 3 ]


In  veterinary medicine  a  bolus  is a large time-release tablet that stays in the  rumen  of  cattle ,  goats , and  sheep . It can also refer to a dose of liquid injected  subcutaneously  with a  hypodermic needle , such as  saline solution  administered either to counteract  dehydration  or especially to mitigate  kidney failure , a common ailment in  domestic cats . Before it is fully absorbed, which can take several minutes or longer, the liquid remains in the form of a  bolus , a ball or lump under the animal's  skin .


In  radiation therapy , bolus is a waxy tissue equivalent material placed on the skin surface to homogenize or modulate the range of the dose from external beams of radiation.


Buccal administration  is a  topical   route of administration  by which  drugs  held or applied in the  buccal  ( / ˈ b ʌ k əl / ) area (in the  cheek ) diffuse through the  oral mucosa  ( tissues  which line the  mouth ) and enter directly into the  bloodstream .  Buccal administration may provide better  bioavailability  of some drugs and a more rapid  onset of action  compared to oral administration because the medication does not pass through the  digestive system  and thereby avoids  first pass metabolism . [ 1 ]  Drug forms for buccal administration include tablets and  thin films .


As of May 2014, the psychiatric drug  asenapine ; the opioid drugs  buprenorphine ,  naloxone , and  fentanyl ; the cardiovascular drug  nitroglycerin ; the nausea medication  prochlorperazine ; the hormone replacement therapy  testosterone ; and  nicotine  as a smoking cessation aid were commercially available in buccal forms, [ 1 ]  as was  midazolam , an  anticonvulsant , used to treat acute  epileptic seizures . [ 2 ]


Buccal administration of  vaccines  has been studied, but there are challenges to this approach due to  immune tolerance  mechanisms that prevent the body from overreacting to  immunogens  encountered in the course of daily life. [ 3 ]


Buccal tablets  are a type of solid  dosage form  administered orally in between the gums and the inner linings of the cheek. [ 4 ]  These  tablets , held within the buccal pouch, either act on the  oral mucosa  or are rapidly absorbed through the buccal mucosal membrane. [ 5 ]  Since drugs "absorbed through the buccal mucosa bypass gastrointestinal  enzymatic  degradation and hepatic  first-pass effect ", [ 6 ]  prescribing buccal tablets is increasingly common among healthcare professionals.


Buccal tablets serve as an alternative drug delivery in patients where compliance is a known issue, including those who are  unconscious ,  nauseated , or having difficulty in swallowing (i.e.  dysphagia ). [ 7 ]  A wide variety of these drugs are available on the market to be prescribed in hospitals and other healthcare settings, including common examples like Corlan, Fentora, and Buccastem.


The most common route for drug transport through the buccal mucosa is the  paracellular  pathway. Most  hydrophilic  drugs permeate the cheek linings via the paracellular pathway through the mechanism of  passive diffusion , and  hydrophobic  drugs are transported through the  transcellular  pathway. [ 7 ]  This route of administration is beneficial for  mucosal  administration and  transmucosal  administration. [ 8 ]  Buccal tablets are typically formulated through the direct compression of drug, powder mixture, swollen polymer, and other agents that assist in processing. [ 8 ]


Buccal tablets offer many advantages in terms of accessibility, ease of administration and withdrawal, and hence may improve  patient compliance . [ 9 ]  Notable drawbacks of buccal tablets include the hazard of choking by involuntarily swallowing the tablet and irritation of the gums. [ 7 ]  Caution should be exercised along with counselling from medical practitioners before use of these tablets.


With recent advances on buccal tablets and in conditions where the conventional oral route (i.e. swallowing of tablet) cannot be delivered effectively, some commonly prescribed buccal tablets available in healthcare settings are listed below as examples.


Hydrocortisone  is a  corticosteroid  that is clinically used to relieve the pain and discomfort of  mouth ulcers  and functions to speed the healing of mouth ulcers. [ citation needed ]  Common side effects include:  oral thrush , visual disturbances (e.g.  blurry vision ), worsening of  diabetes , worsening of mouth  infections , and  allergic reactions  (e.g. skin rash). Hydrocortisone is contraindicated in patients  hypersensitive  to hydrocortisone and those with mouth ulcers caused by  dentures  or infection as it can worsen the severity of mouth ulcers.


Some cautions and remarks include needing to gargle and spit water once tablet is fully dissolved to minimise risk of oral thrush, prolonged use may lead to withdrawal symptoms, chewing and swallowing of the tablet may limit its efficacy and give rise to additional side effects, and caution with  CYP3A4   inhibitors .


Fentanyl  is an  opioid analgesic  used for the treatment of  breakthrough pain  in  cancer  patients who are already receiving and/or are tolerant to maintenance opioid therapy for chronic cancer pain [ 10 ] [ 11 ] [ 12 ]  Common side effects include:  nausea ,  vomiting ,  headache ,  constipation  and  drowsiness . Fentanyl is contraindicated in patients hypersensitive to fentanyl, opioid non-tolerant patients, management of acute or  postoperative  pain, and those with severe  hypotension  or severe obstructive airway diseases (e.g.  COPD )


Some cautions include needing to keep tablets out of the sight and reach of children, and must not be sucked, chewed or swallowed. Other remarks include caution when administered in patients with  hepatic or renal impairment , having drug interactions with CYP3A4 inducers and inhibitors and co-administration with CNS  sedative  agents (e.g.  antihistamines ) will increase CNS side effects.


Prochlorperazine maleate  is under the class of  antiemetics  and  antipsychotics . These buccal tablets are administered for the treatment of severe nausea and vomiting associated with  migraine , [ 13 ] [ 14 ]  as well as managed in symptoms of  schizophrenia . Side effects typically seen in patients using prochlorperazine maleate tablets include drowsiness, blurred vision,  dry mouth , and headache. In rare cases, these tablets may cause serious allergic reactions (i.e.  anaphylaxis ). Prochlorperazine maleate is contraindicated in certain patient groups, including hypersensitivity to prochlorperazine maleate, certain diseases like  glaucoma ,  epilepsy  and  Parkinson's disease . They are also avoided in those with hepatic and  prostate gland  problems.


Special caution is taken in patients with high risk of  blood clot  and  stroke , along with associated risk factors (e.g.  high blood pressure  and  high cholesterol  levels). Those taking prochlorperazine maleate should avoid exposure to direct sunlight due to  photosensitivity  and taken certain drugs that are either sedative and give dry mouth (e.g.  anticholinergics ) or target the heart (e.g.  antihypertensives  and  anticoagulants ). Other remarks include being most effective when taken after food and possible withdrawal symptoms if they are abruptly stopped.


The buccal mucosa, along with the gingival and sublingual mucosa, is part of the  oral mucosa . [ 15 ]  It is composed of non-keratinised tissue. Unlike intestinal and nasal mucosae, it lacks tight junctions and is instead equipped with loose intercellular links of  desmosomes ,  gap junctions  and  hemidesmosomes . [ 7 ]  While it has a less  permeable  effect than  sublingual administration , buccal administration is still capable of creating local or  systemic effects  following drug administration. [ 7 ]  In the oral cavity, buccal tablets potentiate their effect by entering the bloodstream direction through the  internal jugular vein  into the  superior vena cava , [ 8 ]  avoiding acidic  hydrolysis  to take place in the  gastrointestinal tract . [ 16 ]


There are two major routes for drug transportation through the buccal mucosa: transcellular and paracellular pathways. [ 8 ]


Small hydrophobic molecules and other lipophilic compounds mostly move across the buccal mucosa via the transcellular pathway. Drugs are transferred via the transcellular pathway through either  facilitated diffusion  for polar or  ionic compounds ,  diffusion  for low molecular weight molecules, or  transcytosis  and  endocytosis  for macromolecules. [ 8 ]  The physicochemical properties of the drug, for example, its oil/water  partition coefficient ,  molecular weight , structural conformation, determines whether the molecules are transported through the transcellular pathway. [ 8 ]


As the  cell membrane  is  lipophilic , it is more difficult for drugs that are hydrophilic to  permeate  the membrane. Hence, the  excipients  of the formulation and the phospholipid bilayer assist in enhancing the diffusion of hydrophilic compounds (i.e. peptides, proteins, macromolecules). [ 8 ]


Generally, small low-molecular-weight hydrophilic compounds diffuse across the buccal epithelium through the paracellular pathway via passive diffusion. The extracellular  amphiphilic  lipid matrix proves to be a major barrier for  macromolecular  hydrophilic compounds. [ 8 ]  After the administration of the buccal tablet, it must transport either through the epithelial layers to achieve its effect on the systemic circulation (systemic effect) or remain at a target site to elicit a local effect. [ 8 ]


Buccal tablets offer many advantages over other solid dosage forms also intended for oral administration (e.g.  enteric-coated  tablets,  chewable  tablets, and capsules).


Buccal tablets can be considered in patients who experience difficulty in swallowing, since these tablets are absorbed into the blood stream between the gum and cheek. [ 17 ] [ 4 ]  Difficulty in swallowing can occur in all age groups, especially in young infants and the elderly community. [ 18 ]  Buccal tablets are also used in unconscious patients. [ citation needed ]  Additionally, in the case of accidental swallowing of a buccal tablet, adverse effects are minimal as most buccal drugs cannot survive hepatic first-pass metabolism.


Compared to orally ingested capsules and tablets, buccal tablets provide a more rapid  onset of action  because the oral mucosa is highly vascularised. [ 17 ] [ 9 ]  Buccal tablets are also used in emergency situations because they can exert their effects quickly.


Buccal tablets directly enter the systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver. [ 6 ]  As such, patients can take a reduced overall dose to minimise symptoms. In addition, buccal tablets can be removed if adverse reactions appear.


In general, many drugs are not suitable to be delivered via the buccal mucosa due to the small dose criteria. Buccal tablets are rarely used in healthcare settings due to unwanted properties that may limit patient compliance, for example, unpleasant taste and irritation of the oral mucosa. [ 19 ]  These undesired characteristics may lead to accidental swallowing or involuntary expulsion of the buccal tablet. Buccal tablets are also not preferred for drugs that require  extended-release . [ 17 ]


Absorption of drugs via the buccal membrane may not be suitable for all patients. Due to possible undesirable side effects and loss of drug effectiveness, buccal tablets must not be crushed, chewed, or swallowed under any circumstances. As such, buccal tablets are not always appropriate for patients (e.g. individuals on  enteral tube feeding ). It is also noted that eating, drinking or smoking should be avoided until the buccal tablet is fully dissolved to prevent drug efficacy changes and concerns of choking. [ 20 ]


Buccal tablets are dry formulations that attain bioadhesion through dehydrating local mucosal surfaces. [ 7 ]  Many bioadhesive buccal tablet formulations are created through the direct compression method with a release retardant and swollen  polymer , [ 8 ]  and are designed to either release the drug in a unidirectional or multidirectional manner into the saliva. [ 7 ]


Conventional dosage forms are unable to ensure therapeutic drug levels in the circulation and the mucosa for mucosal and transmucosal administration because of the washing effect of saliva, and the mechanical stress of the oral cavity. [ 7 ]  These two mechanisms act as a physiological removal system that removes the formulation from the mucosa, resulting in a decreased exposure time and unpredictable pharmacological profile of the drug's distribution. [ 7 ]


This effect can be countered by prolonging the contact between the  active substance  from the buccal tablet and the mucosa, the tablet should contain: mucoadhesive agents, penetration enhancers,  enzyme inhibitors  and solubility modifiers. [ 7 ]


The mucoadhesive agents assist in the maintenance of prolonged contact between the drug with the absorption site. [ 7 ]  Penetration enhancers improve the ability of the drug to permeate the mucosa for transmucosal delivery or penetrate into the layers of the epithelium for mucosal delivery. Enzyme inhibitors partake in the protection of the drug from mucosal enzyme degradation, and solubility modifiers increase the  solubility  of drugs that are poorly absorbed. [ 7 ]


Cerate , historically  simple cerate , (from  Latin   cera  "wax") is an unctuous preparation for external application, of a consistency intermediate between that of an  ointment  and a  plaster .  It can be spread upon cloth without the use of heat, but does not melt when applied to the skin.


Cerate consists essentially of  wax  (for which  resin ,  lead acetate  or  spermaceti  is sometimes substituted) mixed with oil, lard, and various medicinal ingredients. The cerate of the United States Pharmacopoeia is a mixture of three parts of  paraffin  and seven parts of  lard .


A  depot injection , also known as a  long-acting injectable  ( LAI ), is a term for an  injection  formulation of a medication which  releases slowly over time  to permit less frequent administration of a medication. They are designed to increase  medication adherence  and  consistency , especially in patients who commonly forget to take their medicine. Depot injections can be created by modifying the drug molecule itself, as in the case of  prodrugs , or by modifying the way it is administered, as in the case of oil/lipid suspensions. Depot injections can have a duration of action of one month or greater and are available for many types of drugs, including  antipsychotics  and  hormones .


Depot injections provide longer duration drug action through slow absorption into the bloodstream. They are usually administered  in the muscle ,  into the skin , or  under the skin . The injected medication slowly releases the medication into the bloodstream. It may be used in patients who forget to take their medication; some doctors and patients consider the use of a depot injection to be coercion, and are opposed to their use for that reason. [ 1 ]


Drugs may be modified to be slowly activated by the body, or be absorbed slowly by the body. Many are dissolved in an organic oil, as the compound is  lipophilic  due to the addition of functional groups to provide slow action. An example of this is adding a functional group such as  decanoate . [ 2 ]  The combination of an oil base and modification to decrease metabolic activation prevent medications from being fully released. [ 2 ] [ 3 ]  This can result in length of activity of 2–4 weeks or more. [ 2 ] [ 3 ]


The alteration of the  pharmacokinetics  of the drug (the absorption and activation) does not change the side effect profile of the medication; thus,  atypical antipsychotics  are still preferred over  typical antipsychotics . [ 3 ]


The first long-acting (depot) injections were antipsychotics  fluphenazine  and  haloperidol . [ 2 ]  The concept of a depot injection arose before 1950, and originally was used to describe antibiotic injections that lasted longer to allow for less frequent administration. [ 4 ]


Most commonly, depot injections are designed to have a duration of 2–4 weeks of action, [ 5 ]  however the pharmacokinetics of a specific formulation vary. Absorption and metabolism can both be affected by modifying the drug itself (for example, by attaching a  functional group ) or by the formulation of the product (examples are oil or  microsphere  preparations). [ 5 ]  Repeated administration of depot injections can lead to a half life over one month (as in some preparations of  fluphenazine ), but this can be variable in different patients. [ 6 ]


Hormonal depot injections of  estradiol  can last anywhere from one week to over one month. [ 7 ]   Medroxyprogesterone acetate  is available as a depot injection which is injected once every three months to provide continuous hormonal contraception and releases for up to nine months after injection. [ 8 ]


Many medications are available as depot injections, including many typical and atypical antipsychotics, [ 9 ]  as well as some  hormonal medications  and medication for  opioid use disorder . [ 10 ] [ 11 ] [ 1 ]  Depot injections of antipsychotics are used to improve historically low adherence in patients with diseases such as  schizophrenia . [ 9 ]  Different products may be administered or implanted either by a doctor or nurse, while some are designed to be administered by the patient themselves. [ 12 ]  Self-administered depot injections are used to increase healthcare access and decrease the need to visit the doctor as frequently, especially in  low and middle income countries . [ 12 ]


Insulin  may also be considered a depot injection depending on formulation.  Insulin glargine , for example, is designed to precipitate after injection so it can be slowly absorbed by the body over a longer period than  regular insulin  would be. [ 13 ]  Depot injections of insulins have been studied to better replicate the body's natural  basal  rate of insulin production, and which can be activated by light to control the release of insulin from the injected depot. [ 14 ]


The  dermis  or  corium  is a layer of  skin  between the  epidermis  (with which it makes up the  cutis ) and  subcutaneous tissues , that primarily consists of  dense irregular connective tissue  and cushions the body from stress and strain. It is divided into two layers, the superficial area adjacent to the epidermis called the papillary region and a deep thicker area known as the reticular dermis. [ 1 ]   The dermis is tightly connected to the epidermis through a  basement membrane . Structural components of the dermis are  collagen ,  elastic fibers , and  extrafibrillar matrix . [ 2 ]  It also contains  mechanoreceptors  that provide the sense of  touch  and  thermoreceptors  that provide the sense of  heat . In addition,  hair follicles ,  sweat glands ,  sebaceous glands (oil glands) ,  apocrine glands ,  lymphatic vessels , nerves and  blood vessels  are present in the dermis. Those blood vessels provide nourishment and waste removal for both dermal and epidermal cells.


The dermis is composed of three major types of  cells : [ 3 ]   fibroblasts ,  macrophages , and  mast cells .


Apart from these cells, the dermis is also composed of  matrix  components such as  collagen  (which provides  strength ),  elastin  (which provides  elasticity ), and  extrafibrillar matrix , an extracellular gel-like substance primarily composed of  glycosaminoglycans  (most notably  hyaluronan ),  proteoglycans , and  glycoproteins . [ 3 ]


The  papillary dermis  is the uppermost layer of the dermis. It intertwines with the  rete ridges  of the epidermis and is composed of fine and loosely arranged collagen fibers. [ 2 ]
The papillary region is composed of loose  areolar connective tissue . It is named for its fingerlike projections called  papillae  or  dermal papillae  specifically, that extend toward the epidermis and contain either terminal networks of  blood   capillaries  or tactile  Meissner's corpuscles . [ 4 ]


The dermal papillae (DP) (singular  papilla , diminutive of Latin  papula , 'pimple') are small, nipple-like extensions (or interdigitations) of the dermis into the  epidermis . At the surface of the skin in hands and feet,  they appear as epidermal, papillary or friction ridges (colloquially known as  fingerprints ).


Blood vessels in the dermal papillae nourish all  hair follicles  and bring nutrients and oxygen to the lower layers of epidermal cells. The pattern of ridges produced in hands and feet are partly genetically determined features that are developed before birth. They remain substantially unaltered (except in size) throughout life, and therefore determine the patterns of fingerprints, making them useful in certain functions of personal identification. [ 5 ]


The dermal papillae are part of the uppermost layer of the dermis, the papillary dermis, and the ridges they form greatly increase the surface area between the dermis and epidermis. Because the main function of the dermis is to support the epidermis, this greatly increases the exchange of oxygen, nutrients, and waste products between these two layers. Additionally, the increase in the surface area prevents the dermal and epidermal layers from separating by strengthening the junction between them. With age, the papillae tend to flatten and sometimes increase in number. [ 6 ]


The skin of the hands and fingers and the feet and toes is known by forensic scientists as friction ridge skin. It is known by anatomists as thick skin, volar skin or hairless skin. It has raised ridges, a thicker and more complex epidermis, increased sensory abilities, and the absence of hair and sebaceous glands. The ridges increase friction for improved grasping. [ 7 ]


Dermal papillae also play a pivotal role in hair formation, growth and cycling. [ 8 ]


In  mucous membranes , the equivalent structures to dermal papillae are generally termed "connective tissue papillae", which interdigitate with the  rete pegs  of the superficial epithelium.
Dermal papillae are less pronounced in thin skin areas.


The  reticular dermis  is the lower layer of the dermis, found under the papillary dermis, composed of  dense irregular connective tissue  featuring densely-packed collagen fibers. It is the primary location of dermal elastic fibers. [ 2 ]


The reticular region is usually much thicker than the overlying papillary dermis. It receives its name from the dense concentration of  collagenous ,  elastic , and  reticular fibers  that weave throughout it. These  protein  fibers give the dermis its properties of  strength ,  extensibility , and elasticity. Within the reticular region are the  roots of the hair ,  sebaceous glands ,  sweat glands ,  receptors ,  nails , and blood vessels. The orientation of collagen fibers within the reticular dermis creates lines of tension called  Langer's lines , which are of some relevance in surgery and wound healing. [ 9 ]


Drug delivery to the brain  is the process of passing  therapeutically active molecules  across the  blood–brain barrier  into the  brain . This is a complex process that must take into account the complex anatomy of the brain as well as the restrictions imposed by the special junctions of the blood–brain barrier.


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 . [ 1 ]  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 ". [ 1 ]    The  astrocytes  are  glial cells  restricted to the  brain  and  spinal cord  and help maintain blood-brain barrier properties in brain  endothelial cells . [ 1 ]


The primary 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 and many  ions  from passing between the junction spaces. This forces molecules to go through the endothelial cells to enter the  brain tissue , meaning that they must pass through the  cell membranes  of the  endothelial cells . [ 2 ]
Because of this, the only molecules that can easily transverse the blood–brain barrier are very  lipid - soluble  ones. 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 the normal cellular function of the  brain . [ 3 ]  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. [ 1 ]


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. [ 4 ]  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." [ 4 ]  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. [ 5 ]  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 . [ 6 ]  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. [ 5 ]


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. [ 7 ] [ 8 ] [ 9 ] [ 10 ]


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. [ 11 ]


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 [ 7 ]  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. [ 7 ]  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. [ 7 ]


These are drug compounds that increase the permeability of the blood–brain barrier. [ 12 ]  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. [ 8 ]  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. [ 8 ]


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. [ 5 ]  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. [ 13 ]   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 .


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. [ 14 ]  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. [ 10 ]  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. [ 10 ]   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. [ 10 ]


An  enema , also known as a  clyster , is an injection of fluid into the rectum or into  lower bowel  by way of the  rectum . [ 1 ]  The word  enema  can also refer to the liquid injected, [ 2 ] [ 3 ]  as well as to a device for administering such an injection. [ 4 ]


In standard medicine, the most frequent uses of enemas are to relieve constipation and for bowel cleansing before a medical examination or procedure; [ 5 ]  also, they are employed as a  lower gastrointestinal series  (also called a barium enema), [ 6 ]  to treat  traveler's diarrhea , [ 7 ]  as a vehicle for the administration of food, water or medicine, as a stimulant to the general system, as a local application and, more rarely, as a means of reducing body temperature, [ 1 ]  as treatment for  encopresis , and as a form of  rehydration therapy  (proctoclysis) in patients for whom  intravenous therapy  is not applicable. [ 8 ]


The principal medical usages of enemas are:


As  bowel  stimulants, enemas are employed for the same purposes as orally administered  laxatives : to relieve  constipation ; to treat  fecal impaction ; to empty the colon prior to a medical procedure such as a  colonoscopy . When oral laxatives are not indicated or are not sufficiently effective, enemas may be a sensible and necessary measure. [ 9 ]


A large volume enema [ 10 ]  can be given to cleanse as much of the colon as possible of feces. [ 11 ] [ 12 ]  However, a low enema is generally useful only for stool in the rectum, not in the intestinal tract. [ 13 ]


Such enemas' mechanism consists of the volume of the liquid causing a rapid expansion of the intestinal tract in conjunction with, in the case of certain solutions, irritation of the intestinal  mucosa  which stimulates peristalsis and lubricates the stool to encourage a bowel movement. [ 14 ]  An enema's efficacy depends on several factors including the volume injected and the temperature and the contents of the infusion. [ 9 ]  In order for the enema to be effective the patient should retain the solution for five to ten minutes, as tolerated. [ 5 ] [ 14 ]  or, as some nursing textbooks recommend, for five to fifteen minutes or as long as possible. [ 15 ]


For emptying the entire colon as much as feasible [ 12 ]  deeper and higher enemas are utilized to reach large sections of the colon. [ 9 ]  The colon dilates and expands when a large volume of liquid is injected into it, and the colon reacts to that sudden expansion with general contractions,  peristalsis , propelling its contents toward the rectum. [ 5 ]


Soapsuds enema  is a frequently used synonym for a large volume enema (although soap is not necessary for effectivity). [ 5 ]


For relieving occasional constipation, a large volume enema may be used in a home setting, although for recurring or severe cases of constipation medical care may be required. [ 5 ]


Plain water can be used, simply functioning mechanically to expand the colon, thus prompting evacuation.


Normal saline  is least irritating to the colon. Like plain water, it simply functions mechanically to expand the colon, but having a neutral concentration gradient, it neither draws  electrolytes  from the body, as happens with plain water, nor draws water into the colon, as occurs with phosphates. Thus, a salt water solution can be used when a longer period of retention is desired, such as to soften an impaction.


Castile soap  is commonly added because its irritation of the colon's lining increases the urgency to defecate. [ 15 ]  However, liquid handsoaps and detergents should not be used. [ 5 ]


Glycerol  is a specific bowel mucosa irritant serving to induce peristalsis via a  hyperosmotic effect . [ 16 ]  It is used in a dilute solution, e.g., 5%. [ 17 ]


Equal parts of milk and molasses heated together to slightly above normal body temperature have been used. [ 18 ]  Neither the milk sugars and proteins nor the molasses are absorbed in the lower intestine, thus keeping the water from the enema in the intestine. [ 19 ]  Studies have shown that milk and molasses enemas have a low complication rate when used in the  emergency department [ 20 ]  and are safe and effective with minimal side effects. [ 21 ]


Mineral oil  functions as a lubricant and stool softener, but may have side effects including rectal skin irritation and leakage of oil. [ 22 ]


ATC code A06   Drugs for constipation  is a therapeutic subgroup of the  Anatomical Therapeutic Chemical Classification System , a system of alphanumeric codes developed by the  World Health Organization  (WHO) for the classification of  drugs  and other medical products. [ 23 ] [ 24 ] [ 25 ]  Subgroup A06 is part of the anatomical group  A  Alimentary tract and metabolism . [ 26 ]


Codes for  veterinary  use ( ATCvet codes ) can be created by placing the letter Q in front of the human ATC code: for example,  QA06 . [ 27 ]   National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version.


In alphabetical order


In alphabetical order of the original brand names


Klyx contains  docusate sodium  1 mg/mL and sorbitol solution (70%)(crystallising) 357 mg/mL and is used for faecal impaction or constipation or for colon evacuation prior medical procedures, [ 44 ]  developed by  Ferring B.V.


Micralax (not to be confused with MICROLAX®) [ 45 ]


MICROLAX®  (not to be confused with Micralax) combines the action of  sodium citrate , a peptidising agent which can displace bound water present in the faeces, with sodium alkyl sulphoacetate, a wetting agent, and with glycerol, an anal mucosa irritant and hyperosmotic. However, also sold under the name "Micralax", is a preparation containing  sorbitol  rather than glycerol; [ 46 ]  which was initially tested in preparation for  sigmoidoscopy . [ 47 ]


Micolette Micro-enema® contains 45 mg sodium lauryl sulphoacetate, 450 mg per 5 ml sodium citrate BP, and 625 mg glycerol BP [ 48 ]  and is a small volume stimulant enema suitable where large-volume enemas are contra-indicated. [ 28 ]


TAI , also termed  retrograde irrigation , is designed to assist evacuation using a water enema [ 49 ]  as a treatment for persons with bowel dysfunction, including  fecal incontinence  or constipation, especially  obstructed defecation . By regularly emptying the bowel using transanal irrigation, [ 50 ]  controlled bowel function is often re-established to a high degree, thus enabling development of a consistent bowel routine. [ 50 ]   Its effectiveness varies considerably, some individuals experiencing complete control of incontinence but others reporting little or no benefit. [ 49 ]


An international consensus on when and how to use transanal irrigation for people with bowel problems was published in 2013, offering practitioners a clear, comprehensive and simple guide to practice for the emerging therapeutic area of transanal irrigation. [ 50 ]


The term  retrograde irrigation  distinguishes this procedure from the  Malone antegrade continence enema , where irrigation fluid is introduced into the colon proximal to the anus via a surgically created irrigation port. [ 51 ]


Patients who have a bowel disability, a medical condition which impairs control of  defecation , e.g., fecal incontinence or constipation, [ 52 ]  can use bowel management techniques to choose a predictable time and place to evacuate. [ 52 ]  Without bowel management, such persons might either suffer from the feeling of not getting relief, or they might soil themselves. [ 52 ]


While simple techniques might include a controlled  diet  and establishing a toilet routine, [ 52 ]  a daily enema can be taken to empty the colon, thus preventing unwanted and uncontrolled bowel movements that day. [ 53 ]


In a  lower gastrointestinal series  an enema that may contain  barium sulfate  powder or a water-soluble  contrast agent  is used in the  radiological  imaging of the bowel. Called a  barium enema , such enemas are sometimes the only practical way to  view  the colon in a relatively safe manner. [ 6 ]


Failure to expel all of the barium may cause constipation or possible impaction [ 54 ]  and a patient who has no bowel movement for more than two days or is unable to pass gas rectally should promptly inform a physician and may require an enema or laxative. [ 55 ]


The administration of substances into the bloodstream. This may be done in situations where it is undesirable or impossible to deliver a medication by mouth, such as  antiemetics  given to reduce  nausea  (though not many antiemetics are delivered by enema). Additionally, several anti-angiogenic agents, which work better without digestion, can be safely administered via a gentle enema.


The topical administration of medications into the rectum, such as  corticosteroids  and  mesalazine  used in the treatment of  inflammatory bowel disease . Administration by enema avoids having the medication pass through the entire  gastrointestinal tract , therefore simplifying the delivery of the medication to the affected area and limiting the amount that is absorbed into the bloodstream.


Rectal corticosteroid enemas are sometimes used to treat mild or moderate ulcerative colitis. They also may be used along with systemic (oral or injection) corticosteroids or other medicines to treat severe disease or mild to moderate disease that has spread too far to be treated effectively by medicine inserted into the rectum alone.


Improper administration of an enema can cause electrolyte imbalance (with repeated enemas) or ruptures to the bowel or rectal tissues which can be unnoticed as the rectum is insensitive to pain, [ 66 ]  resulting in internal  bleeding . However, these occurrences are rare in healthy,  sober  adults. Internal bleeding or rupture may leave the individual exposed to infections from intestinal bacteria. Blood resulting from tears in the colon may not always be visible, but can be distinguished if the feces are unusually dark or have a red hue. If intestinal rupture is suspected, medical assistance should be obtained immediately. [ 14 ]  Frequent use of enemas can cause laxative dependency. [ 67 ]


The enema tube and solution may stimulate the  vagus nerve , which may trigger an  arrhythmia  such as  bradycardia .


Enemas should not be used if there is an undiagnosed  abdominal pain  since the peristalsis of the bowel can cause an inflamed  appendix  to  rupture .


There are arguments both for and against colonic irrigation in people with  diverticulitis ,  ulcerative colitis ,  Crohn's disease , severe or internal  hemorrhoids  or  tumors  in the rectum or  colon , and its usage is not recommended soon after bowel  surgery  (unless directed by one's  health care provider ). Regular treatments should be avoided by people with  heart disease  or  kidney failure . Colonics are inappropriate for people with bowel, rectal or anal  pathologies  where the pathology contributes to the risk of  bowel perforation . [ 68 ]


Recent research has shown that ozone water, which is sometimes used in enemas, can immediately cause  microscopic colitis . [ 69 ]


A recent case series [ 70 ]  of 11 patients with five deaths illustrated the danger of phosphate enemas in high-risk patients.


Enema  entered the English language c. 1675 from Latin in which, in the 15th century, [ 3 ]  it was first used in the sense of a rectal injection, [ 2 ]  from Greek ἔνεμα (énema), "injection", itself from ἐνιέναι (enienai) "to send in, inject", from ἐν (en), "in" + ἱέναι (hienai), "to send, throw". [ 71 ]


Clyster  entered the English language in the late 14th century from Old French or Latin, from Greek κλυστήρ (klyster), "syringe", itself from κλύζειν (klyzein), "to wash out", [ 72 ]  also spelled  glister  in the 18th century, [ 73 ]  is a generally archaic word used more particularly for enemas administered using a  clyster syringe .


The first mention of the enema in medical literature is in the Ancient Egyptian  Ebers Papyrus  ( c.  1550  BCE). One of the many types of medical specialists was a Nery-Pehuyt, the Shepherd of the Anus. Many medications were administered by enemas. [ 74 ]  There was a Keeper of the Royal Rectum [ 75 ]  who may have primarily been the pharaoh's enema maker. The god  Thoth , according to Egyptian mythology, invented the enema. [ 76 ]


In parts of Africa the  calabash  gourd is used traditionally to administer enemas. On the Ivory Coast the narrow neck of the gourd filled with water is inserted the patient's rectum and the contents are then injected by means of an attendant's forcible oral inflation, or, alternatively, a patient may self-administer the enema by using suction to create a negative pressure in the gourd, placing a finger at the opening, and then upon anal insertion, removing the finger to allow atmospheric pressure to effect the flow. In South Africa,  Bhaca  people used an ox horn to administer enemas. [ 77 ]  Along the upper Congo River an enema apparatus is made by making a hole in one end of the gourd for filling it, and using a resin to attach a hollow cane to the gourd's neck. The cane is inserted into the anus of the patient who is in a posture that allows gravity to effect infusion of the fluid. [ 78 ]


The  Olmec  from their middle preclassic period (10th through 7th centuries BCE) through the Spanish Conquest used trance-inducing substances ceremonially, and these were ingested via, among other routes, enemas administered using jars.


As further described below in  religious rituals , the  Maya  in their late classic age (7th through 10th centuries CE) used enemas for, at least, ritual purposes, Mayan sculpture and ceramics from that period depicting scenes in which, injected by syringes made of gourd and clay, ritual hallucinogenic enemas were taken. [ 79 ]  In the Xibalban court of the God D, whose worship included ritual cult paraphernal, the Maya illustrated the use of a characteristic enema bulb syringe by female attendants administering clysters ritually. [ 80 ] [ 81 ]


For combating illness and discomfort of the digestive tract, the Mayan also employed enemas, as documented during the colonial period, e.g., in the  Florentine Codex . [ 79 ]


The  indigenous peoples of North America  employed  tobacco smoke enemas  to stimulate respiration, injecting the smoke using a rectal tube. [ 82 ] [ 83 ]


A rubber bag connected with a conical nozzle, at an early period, was in use among the  indigenous peoples of South America   as an enema syringe, [ 84 ]  and the rubber enema bag with a connecting tube and ivory tip remained in use by them while in Europe a syringe was still the usual means for conducting an enema. [ 85 ]


In Babylonia, by 600 BCE, enemas were in use, although it appears that initially they were in use because of a belief that the demon of disease would, by means of an enema, be driven out of the body. [ 86 ]  Babylonian and Assyrian tablets c. 600 BCE bear cuneiform inscriptions referring to enemas. [ 87 ]


In China, c. 200 CE,  Zhang Zhongjing  was the first to employ enemas. "Secure a large pig's bile and mix with a small quantity of vinegar. Insert a bamboo tube three or four inches long into the rectum and inject the mixture" are his directions, according to  Wu Lien-teh . [ 88 ]


In India, in the fifth century BCE,  Sushruta  enumerates the enema syringe among 121 surgical instruments described. Early Indian physicians' enema apparatus consisted of a tube of bamboo, ivory, or horn attached to the scrotum of a deer, goat, or ox. [ 86 ]


In Persia,  Avicenna  (980–1037 A. D.) is credited with the introduction of the "clyster-purse" or collapsible portion of an enema outfit made from ox skin or silk cloth and emptied by squeezing with the hands. [ 87 ]


Hippocrates  (460–370 BCE) frequently mentions enemas, e.g., "if the previous food which the patient has recently eaten should not have gone down, give an enema if the patient be strong and in the prime of life, but if he be weak, a suppository should be administered, should the bowels be not well moved on their own accord." [ 89 ]


In the first century BCE the  Greek physician   Asclepiades of Bithynia  wrote "Treatment consists merely of three elements: drink, food, and the enema". [ 90 ]  Also, he contended that indigestion is caused by particles of food that are too big and his prescribed treatment was proper amounts of food and wine followed by an enema which would remove the improper food doing the damage. [ 91 ]


In the second century CE the Greek physician  Soranus  prescribed, among other  techniques , enemas as a safe  abortion  method, [ 92 ]  and the Greek philosopher  Celsus  recommended an enema of pearl barley in milk or rose oil with butter as a nutrient for those with dysentery and unable to eat, [ 93 ]  and also Galen mentions enemas in several contexts. [ 61 ]


In medieval times appear the first illustrations of enema equipment in the  Western world , a clyster syringe consisting of a tube attached to a pump action bulb made of a pig bladder. [ citation needed ]
A simple piston  syringe  clyster was in use from the 15th through 19th centuries. This device had its rectal nozzle connected to a syringe with a plunger rather than to a bulb. [ citation needed ]


Beginning in the 17th century enema apparatus was chiefly designed for self-administration at home and many were French as enemas enjoyed wide usage in France. [ 93 ]


In 1694  François Mauriceau  in his early-modern treatise,  The Diseases of Women with Child,  records that both midwives and man-midwives commonly administered clysters to labouring mothers just prior to their delivery. [ 94 ]


Clysters were administered for symptoms of constipation and, with more questionable effectiveness, stomach aches and other illnesses. [ when? ] [ citation needed ] [ 95 ]


In 1753 an enema bag prepared from a pig's or beef's bladder attached to a tube was described by Johann Jacob Woyts as an alternative to a syringe. [ 96 ]


In the 18th century Europeans began emulating the  indigenous peoples of North America's  use of tobacco smoke enemas to resuscitate drowned people. [ 97 ]  Tobacco resuscitation kits consisting of a pair of bellows and a tube were provided by the Royal Humane Society of London and placed at various points along the Thames. [ 93 ]  Furthermore, these enemas came to be employed for headaches, respiratory failure, colds, hernias, abdominal cramps, typhoid fever, and cholera outbreaks. [ 97 ]


Clysters were a favourite medical treatment in the  bourgeoisie  and  nobility  of the Western world up to the 19th century. As medical knowledge was fairly limited at the time, purgative clysters were used for a wide variety of  ailments , the foremost of which were  stomach aches  and constipation. [ 9 ]


According to  the duc de Saint-Simon , clysters were so popular at the court of King  Louis XIV of France  that  the duchess of Burgundy  had her servant give her a clyster in front of the King (her modesty being preserved by an adequate posture) before going to the  comedy . However, he also mentions the astonishment of the King and Mme de Maintenon that she should take it before them. [ 98 ]


In the 19th century many new types of enema administration equipment were devised. Devices allowing gravity to infuse the solution, like those mentioned above used by South American indigenous people and like the enema bag described by Johann Jacob Woyts, came into common use. These consist of a nozzle at the end of a hose which connects a reservoir, either a bucket or a rubber bag, which is filled with liquid and held or hung above the recipient. [ 93 ]


In the early 20th century the disposable  microenema , a squeeze bottle, was invented by  Charles Browne Fleet . [ 99 ]


The term "colonic irrigation" is commonly used in  gastroenterology  to refer to the practice of introducing water through a colostomy or a surgically constructed conduit as a treatment for constipation. [ 100 ]  The  Food and Drug Administration  has ruled that colonic irrigation equipment is not approved for sale for the purpose of general well-being [ 101 ]  and has taken action against many distributors of this equipment, including a  Warning Letter . [ 102 ]


The same term is also used in  alternative medicine  where it may involve the use of substances mixed with water in order to  detoxify  the body. Practitioners believe the accumulation of fecal matter in the large intestine leads to ill health. [ 103 ]   This resurrects the old medical concept of  autointoxication  which was orthodox doctrine up to the end of the 19th century but which has now been discredited. [ 104 ] [ 105 ] [ 106 ]


In the late 19th century Dr.  John Harvey Kellogg  made sure that the bowel of each and every patient was plied with water, from above and below. His favorite device was an enema machine ("just like one I saw in Germany") that could run fifteen gallons of water through a person's bowel in a matter of seconds. Every water enema was followed by a pint of yogurt—half was eaten, the other half was administered by enema "thus planting the protective germs where they are most needed and may render most effective service." The yogurt served to replace "the intestinal flora" of the bowel, creating what Kellogg claimed was a completely clean intestine. [ 107 ]


Chlorine dioxide  enemas have been fraudulently marketed as a medical treatment, primarily for  autism . This has resulted, for example, in a six-year-old boy needing to have his colon removed and a colostomy bag fitted, [ 108 ] [ 109 ]  complaints to the FDA reporting life-threatening reactions, [ 110 ]  and even death. [ 111 ]


Proponents falsely claim that administering autistic children these enemas results in the expulsion of parasitic worms (" rope worms "), which actually are fragments of damaged intestinal  epithelium  that are misinterpreted as being human pathogens. [ 112 ] [ 113 ]  Oral and rectal use of the solution has also been promoted as a cure for  HIV ,  malaria ,  viral hepatitis ,  influenza ,  common colds ,  acne ,  cancer ,  Parkinson's , and much more.


Chlorine dioxide is a potent and toxic bleach [ 114 ]  that is relabeled for "medicinal purposes" to a variety of brand names including, but not limited, to MMS,  Miracle Mineral Supplement , and CD protocol. [ 115 ]  For oral use, the doses recommended on the labeling can cause nausea, vomiting, diarrhea, and potentially life-threatening dehydration. [ 116 ]


No clinical trials have been performed to test the health claims made for chlorine dioxide, which originate from former  Scientologist  Jim Humble [ 117 ]  in his 2006  self-published  book,  The Miracle Mineral Solution of the 21st Century [ 118 ]  and from anecdotal reports. The name MMS was coined by Humble. Sellers sometimes describe MMS as a  water purifier  so as to circumvent medical regulations. [ 119 ]  The  International Federation of Red Cross and Red Crescent Societies  rejected "in the strongest terms" reports by promoters of MMS that they had used the product to fight malaria. [ 120 ]


Well documented as having no proven benefits and considered by medical authorities as rash and potentially dangerous is an enema of  coffee . [ 104 ] [ 121 ]


A coffee enema can cause numerous maladies including  infections ,  sepsis  (including  campylobacter  sepsis), severe  electrolyte imbalance ,  colitis , polymicrobial enteric sepsis,  proctocolitis ,  salmonella ,  brain abscess , and heart failure, [ 122 ] [ 123 ] [ 124 ] [ 125 ] [ 126 ] [ 127 ] [ 128 ] [ 129 ] [ 130 ] [ excessive citations ]


and deaths related to coffee enemas have been documented. [ 131 ]


Gerson therapy  includes administering enemas of coffee, [ 132 ]  as well as of  castor oil  and sometimes of  hydrogen peroxide  or of  ozone . [ 133 ]


Some proponents of alternative medicine have claimed that coffee enemas have an anti- cancer  effect by "detoxifying" metabolic products of tumors [ 122 ]  but there is no medical scientific evidence to support this. [ 121 ] [ 123 ] [ 134 ]


Enjoyment of enemas is known as  klismaphilia , which medically is classified as a  paraphilia . [ 135 ] [ 136 ]  A person with klismaphilia is a  klismaphile .


Both women and men may enjoy sexual enema play, heterosexually and homosexually, experiencing  sexual arousal  from enemas which they find gratifying or sensual [ 137 ] [ 138 ]  and which can be an auxiliary to, or even a substitute for, genital  sexual activity . [ 137 ] [ 138 ]


Klismaphiles may perceive pleasure from a large, water-distended belly, or the feeling of internal pressure. An enema fetish may include sexual attraction to the involved equipment, processes, environments, situations, or scenarios, [ 139 ]  Klismaphiles can gain satisfaction of enemas through fantasies, by actually receiving or giving one, or through the process of eliminating steps to being administered one (e.g., under the pretence of being constipated). [ 138 ]


That some women use enemas while masturbating was documented by  Alfred Kinsey  in  Sexual Behavior in the Human Female : "There were still other masturbatory techniques which were regularly or occasionally employed by some 11 percent of the females in the sample... Douches, streams of running water, vibrators, urethral insertions, enemas, other anal insertions, sado-masochistic activity, and still other methods were occasionally employed, but none of them in any appreciable number of cases." [ 140 ]


Besides klismaphilia, the intrinsic enjoyment of enemas, there are other uses of enemas in sexual play. [ 141 ]


Enemas are sometimes used in  sadomasochistic  activities [ 142 ] [ 143 ]  for  erotic humiliation [ 144 ]  or for physical discomfort. [ 145 ]


Another sexual use for enemas is to empty the rectum as a prelude to other anal sexual activities such as  anal sex , [ 146 ]  possibly reducing risk of infection.


This is different from klismaphilia, in which the enema is enjoyed for itself and as a part of sexual arousal and gratification. [ 146 ]


Rectal douching is a common practice among people who take a receptive role in anal sex [ 147 ]  although rectal douching before anal sex may increase the risk of transferring  HIV , [ 148 ]   hepatitis B , [ 149 ]  and other diseases. [ 150 ]


Noting that deaths have been reported from  alcohol poisoning  via enemas, [ 151 ]  an  alcohol enema  can be used to very quickly instill alcohol into the bloodstream, absorbed through the membranes of the colon. However, great care must be taken as to the amount of alcohol used. Only a small amount is needed as the intestine absorbs the alcohol far more quickly than the stomach.


Preceding an enema for administration of drugs or alcohol, a cleansing enema may first be used for cleaning the colon to help increase the rate of absorption. [ 152 ]


All across  Mesoamerica  ritual enemas were employed to consume psychoactive substances, e.g.,  balché ,  alcohol ,  tobacco ,  peyote , and other  hallucinogenic drugs  and  entheogens , most notably by the  Maya , thus attaining more intense trance states more quickly, and Mayan classic-period sculpture and ceramics depict hallucinogenic enemas used in rituals. [ 79 ]  Some tribes continue the practice in the present day. [ 153 ]


With historical roots in the  Indian subcontinent , enemas in  Ayurveda , called  Basti  or Vasti, form part of  Panchakarma  procedure in which  herbal medicines  are introduced rectally. [ 154 ]


Enemas have also been forcibly applied as a means of punishment.


Political dissenters in post-independence Argentina were given enemas of  chili pepper  and  turpentine . [ 155 ]  Turpentine enemas are very harsh purgatives. [ 156 ]


In the  Guantanamo Bay Detention Camp , the  Senate Intelligence Committee report on CIA torture  documented instances of enemas being used by the  Central Intelligence Agency  in order to ensure "total control" over detainees. [ 157 ]  Enemas, officials said, are uncomfortable and degrading, [ 158 ]  The CIA forced nutrient enema on detainees who attempted hunger strikes, documenting "With head lower than torso … sloshing up the large intestines … [what] I infer is that you get a tube up as you can … We used the largest Ewal  [ sic ] tube we had" wrote an officer, [ 159 ]  and "violent enemas" is how a detainee described what he received. [ 160 ]


In the  Dionysus '  satyr play   Limos ,  Silenus  attempts to give an enema to  Heracles . [ 161 ]


In  Cervantes '  Don Quixote , a narrative to Sancho includes “The Knight of the Sun ... bound hand and foot ... was administered a clyster of snow water and sand that almost disracted him" [ 162 ]


In the 17th century, satirists made physicians a favorite target, resembling  Molière 's caricature whose prescription for anything was "clyster, bleed, purge," or "purge, bleed, clyster". [ 163 ]


In Molière's play  The Imaginary Invalid , Argan, a severe  hypochondriac , is addicted to enemas as indicated by such lines as when Bĕralde asks, "Can't you be one moment without a purge?" [ 164 ]


In  Grace Metalious 's novel  Peyton Place , the town doctor tells of "a young boy with the worst case of dehydration I ever saw. It came from getting too many enemas that he didn't need. Sex, with a capital S-E-X.". [ 165 ]  As a teenager, the boy enjoys receiving enemas from his mother. [ 166 ]


In  Flora Rheta Schreiber 's book  Sybil , Sybil's psychiatrist asks her "What's Mama been doing to you, dear?...I know she gave you the enemas." [ 167 ]


In  The Right Stuff , during flight training astronaut  Alan Shepard  retains a barium enema, [ 168 ]  given two floors away from a toilet, embarrassedly riding a public elevator wearing a  hospital gown  and holding the enema bag with its tip still inserted in him. [ 169 ] [ 170 ]


Water Power  is a film loosely based on the real-life exploits of  Michael H. Kenyon , an American criminal who pleaded guilty to a decade-long series of armed robberies of female victims, some of which involved sexual assaults in which he would give them enemas. [ 171 ]


The lyrics of  Frank Zappa 's song  The Illinois Enema Bandit  are concerned with  Michael H. Kenyon 's  sexual assaults  which included administering involuntary enemas. [ 172 ]


A 365-kilogram (805-pound) brass statue of a syringe enema bulb held aloft by three cherubs stands in front of the "Mashuk" spa in the settlement of  Zheleznovodsk  in Russia. Inspired by the 15th century Renaissance painter Botticelli, it was created by a local artist who commented that "An enema is an unpleasant procedure as many of us may know. But when cherubs do it, it's all right." When unveiled on 19 June 2008, posted on one of the spa's wall was a banner declaring "Let's beat constipation and sloppiness with enemas."  The spa lying in the Caucasus Mountains region, known for dozens of spas that routinely treat digestive and other complaints with enemas of mineral spring water, the director commented "An enema is almost a symbol of our region." [ 173 ] [ 174 ]  It is the only known monument to the enema. [ 175 ]


Sources


"A professional nursing instructional video demonstrating administering a cleansing enema" .  Taber's Medical Dictionary . K. A. Davis Company . Retrieved  17 July  2014 .


Enteral  administration is food or  drug administration  via the  human gastrointestinal tract . This contrasts with  parenteral  nutrition or drug administration (Greek  para , "besides" +  enteros ), which occurs from routes outside the GI tract, such as  intravenous  routes. Enteral administration involves the esophagus, stomach, and small and large intestines (i.e., the gastrointestinal tract). Methods of administration include oral, sublingual (dissolving the drug under the tongue), and rectal. Parenteral administration is via a peripheral or central vein. [ 1 ]  In  pharmacology , the route of drug administration is important because it affects  drug metabolism ,  drug clearance , and thus  dosage . The term is from  Greek   enteros  'intestine'.


Enteral administration may be divided into three different categories, depending on the entrance point into the GI tract: oral (by  mouth ), gastric (through the  stomach ), and rectal (from the  rectum ). (Gastric introduction involves the use of a tube through the nasal passage ( NG tube ) or a tube in the belly leading directly to the stomach ( PEG tube ). Rectal administration usually involves rectal  suppositories .)


The mechanism for drug absorption from the intestine is for most drugs passive transfer, a few exceptions include  levodopa  and  fluorouracil , which are both absorbed through  carrier-mediated transport . For  passive transfer  to occur, the drug has to diffuse through the lipid  cell membrane  of the  epithelial cells  lining the inside of the intestines. The rate at which this happens is largely determined by two factors:  Ionization  and  lipid solubility . [ 2 ]


Factors influencing gastrointestinal absorption:


Drugs given by enteral administration may be subjected to significant  first pass metabolism , and therefore, the amount of drug entering the systemic circulation following administration may vary significantly for different individuals and drugs. Rectal administration is not subject to extensive first pass metabolism.


Focused ultrasound for intracrainial drug delivery  is a  non-invasive technique  that uses  high-frequency  sound waves ( focused ultrasound , or FUS) to disrupt tight junctions in the  blood–brain barrier  (BBB), allowing for increased passage of  therapeutics  into the brain. The BBB normally blocks nearly 98% of drugs from accessing the central  nervous system , so FUS has the potential to address a major challenge in intracranial drug delivery by providing targeted and reversible BBB disruption. Using FUS to enhance  drug delivery to the brain  could significantly improve patient outcomes for a variety of diseases including  Alzheimer's disease ,  Parkinson's disease , and  brain cancer .


Ultrasound  is commonly used in the medical field for imaging and diagnostic purposes. With FUS, a curved  transducer ,  lens , or phased array is used to guide the ultrasound waves to a particular location, similar to the way a magnifying glass can focus sunlight to a single point. [ 1 ]  This strategy concentrates the acoustic energy in a small target area while having a minimal effect on the surrounding tissue. [ 2 ]  Depending on the acoustic parameters, FUS can be used to exert mechanical and/or thermal effects on target tissues, making it a versatile and promising tool for many therapeutic applications.


The BBB is a highly specialized structure composed of  endothelial cells ,  pericytes , and  astrocytic  processes and is situated between the  cerebral  capillaries and brain  parenchyma . The  endothelial  cells form tight junctions, creating a semi- permeable membrane  that separates
circulating blood from the  central nervous system . Various mechanisms are used to transport molecules across the BBB. Small polar molecules such as  glucose ,  amino acids , and  nucleosides  enter the brain through carrier-mediated transport. Small  lipophilic molecules  and
gaseous molecules such as oxygen and carbon dioxide can passively diffuse through the BBB. Large molecules such as  proteins  and  peptides  use receptor-mediated or absorption-mediated  endocytic transport  to access the brain. [ 3 ]


The BBB is crucial for structural and functional brain connectivity and plays a major role in protecting the brain from circulating  pathogens . [ 4 ]  However, the BBB is also a key impediment
for intracranial drug delivery and significantly limits entry of therapeutic molecules into the brain. Generally, only  lipid -soluble molecules with a low  molecular weight  (around ~400 Da) and a positive charge can cross the BBB. [ 5 ]  Many therapeutic molecules do not have these properties and thus have difficulty entering the brain. For example,  doxorubicin , a common
 chemotherapeutic , is ~540 Da in size and  trastuzumab , a  monoclonal antibody , is 148 kDa in size. [ 6 ]  The molecular weight of these molecules significantly hinders their ability to pass through the tight junctions present in the BBB.


Since the BBB limits the  bioavailability  of therapeutics in treating neurological diseases, many strategies have been developed to circumvent the BBB.  Osmotic  agents disrupt the BBB by causing osmotic shrinkage of the  endothelial  cells and creating an osmotic pressure gradient. [ 7 ]  However, this strategy results in global rather than localized BBB opening which can lead to neurological deficits and  seizures . [ 8 ]  Intracranial injections can be used to directly deliver drugs to a specific part of the brain. [ 9 ]  While these injections limit systemic toxicities and remove the
loss of drug from first pass clearance, these procedures are invasive and can pose additional risk to the patient.  Convection  enhanced delivery uses an intracranial  catheter  to deliver drug through the interstitial spaces of the central nervous system. This strategy is also quite invasive as it requires insertion of the catheter into the brain and the diffusion of drug from the catheter tip is limited. [ 10 ]   Radiation therapy  is known to increase BBB permeability, but the temporal characteristics of radiation-induced opening are unpredictable and radiation can damage the surrounding brain tissue by causing  necrosis ,  demyelination , and  gliosis . [ 11 ]  Focused ultrasound has the potential to address the limitations posed by these strategies by offering a
method for non-invasive, temporally-controlled, and localized BBB disruption.


Early studies that investigated the use of FUS for BBB disruption used ultrasound to increase the  permeability of the blood vessels  either by increasing the temperature (usually to 40-45°C) or forming gas bubbles (inertial  cavitation ). While these studies concluded that this method could be used to open the BBB, damage to healthy  tissue  was always reported. [ 12 ]   In 2004, it was discovered that the threshold for thermal BBB disruption is greater than the threshold for thermal damage, meaning thermal BBB disruption cannot be performed without causing some damage to the brain tissue. Nevertheless, ultrasound  hyperthermia  may still be useful for intracranial drug delivery. In vitro studies showed that moderate ultrasound hyperthermia (temperature elevations ≤ 6°C) increases endothelial cell permeability to  hydrophobic  molecules. [ 13 ]  FUS hyperthermia has also been used with radiation therapy to treat patients with brain  tumors  since FUS sensitizes tumor cells to radiation by inhibiting  DNA damage repair  and disrupting the  protein kinase B   signaling pathway . [ 14 ] [ 15 ]  Studies have also shown that FUS can be used to both thermally  ablate  brain tumors and improve delivery of  chemotherapy  through reversible BBB opening to kill any remaining  malignant  cells. [ 16 ]  However, since thermal BBB disruption cannot be induced without damaging tissue, it may not be useful for non-cancer applications in which preserving healthy tissue may be essential.


Cavitation  occurs when gas bubbles grow, oscillate, and collapse in a fluid during exposure to ultrasound waves. There are two general types of cavitation: stable and inertial. Stable cavitation occurs when the gas bubbles oscillate, and these oscillations are sustained for many cycles of acoustic pressure. [ 17 ]  These oscillations move the surrounding fluid, generating flow around the bubble. This flow is known as microstreaming and can increase the amount of drug that passes through the openings in the tight junctions. Inertial cavitation is typically transient and results in the collapse or fragmentation of bubbles. Low acoustic pressures are used to induce stable cavitation while higher ultrasound intensities lead to inertial cavitation. Both stable and inertial cavitation apply mechanical stress to the blood vessel walls, temporarily disrupting the tight junctions between the endothelial cells. [ 18 ]  This is typically done through a push-pull action in which the bubble expansion separates the endothelial lining while the bubble contraction causes  invagination  of the  vascular  lining. Transiently disrupting the BBB allows for  paracellular transport  of molecules, and there is evidence that the physical stress induced on the vessel walls by the gas bubbles causes cellular changes that further enhance paracellular and  transcellular  transport of therapeutics across the BBB. [ 19 ]  However, this mechanical stress can damage the blood vessels, and inertial cavitation is generally avoided for BBB opening since it poses the greatest risk for injury. [ 20 ]


Due to the safety and efficacy issues related to thermal and cavitation-assisted FUS-induced BBB opening, research has focused on using preformed  microbubbles  to further enhance the effects of FUS. Microbubbles are small bubbles with diameters typically between .5 and 10  microns . The core is typically filled with gas, but microbubbles can also be loaded with active drug for therapeutic purposes. The microbubble shell is typically composed of  polymers , lipids,  proteins , or a combination of these components. Since these microbubbles are  lipophilic , they
can diffuse through the BBB. In 2001, Hynynen et al. used microbubbles in conjunction with FUS to induce BBB opening without causing tissue damage. [ 21 ]  By injecting microbubbles into the blood before sonication, they found the intensities required to disrupt the BBB were two times lower than the intensity required with FUS alone. Furthermore, they discovered that the BBB was restored 24 hours after the FUS treatment. Following this study, several groups have
reported effective intracranial drug delivery using microbubbles with different FUS parameters. Many researchers have concluded that ultrasound pressure is the most important parameter to optimize to avoid injuring blood vessels and surrounding brain tissue. [ 22 ]  It has been seen that greater ultrasound pressure is required to allow a 2000 kDa drug to cross the BBB compared to a 70 kDa drug. [ 23 ]  In rodent models, it has been shown that BBB disruption with microbubbles
is effective over a wide range of ultrasound frequencies from 28 kHz to 8 MHz. [ 24 ]  While the repetition frequency of the ultrasound bursts do not significantly affect BBB opening, if the burst frequency is too high, the microbubbles cannot effectively reperfuse the target area. [ 25 ]  The properties of the microbubbles themselves can affect treatment efficacy. As microbubble size and dose increase, BBB opening increases and there is a greater risk for damage. [ 26 ]


Microbubbles can also serve as effective drug carriers. Drugs can be adhered to the surface of microbubbles, encapsulated inside the microbubble, or embedded in the microbubble membrane. [ 27 ]   Ligands  can also be conjugated to the surface of microbubbles to target specific sites. [ 28 ]  FUS-induced cavitation can be used to burst the microbubbles and release drug near the diseased region. This method achieves local drug release while limiting off-target toxicities. [ 29 ]  Drug-loaded microbubbles with FUS has been shown to be an attractive combination  therapy  for brain tumors. One study found that the ultrasound-triggered release of  doxorubicin  from loaded microbubbles resulted in a two-fold decrease in human  glioblastoma  cell survival rate compared to free doxorubicin or loaded microbubbles without FUS. [ 30 ]  Another study found encapsulating  carmustine  in microbubbles led to a five-fold increase in the circulating half-life and a five-fold decrease in drug accumulation in the liver. [ 31 ]  This study also found combining these carmustine-loaded microbubbles with FUS increased the median survival time by 12% in a rat  glioma  model. Due to the promising results seen with drug-loaded microbubbles and FUS for brain tumor treatment, this method may also have potential for treating other neurological disorders such as Alzheimer's and  Parkinson's  disease. [ 32 ] [ 33 ]


FUS for intracranial drug delivery has many potential benefits for both cancer and non-cancer applications. Examples of studies that used FUS to deliver therapeutics into the brain are summarized below.


While FUS has many potential advantages for intracranial drug delivery, there are several limitations. Heterogeneity in the acoustic properties of the  skull  leads to distortion and attenuation of the ultrasound. Intracranial structures such as gray and  white matter  and dense  vasculature  also vary between patients, so each individual may have a unique threshold for BBB opening. Patient-specific ultrasound arrays may need to be used to address this concern. After the procedure,  MRI contrast agents  are given to patients to measure BBB opening, so currently there is no method for intraoperative monitoring of BBB disruption. For strategies that use  magnetic resonance guidance , the need for pre-procedural removal of hair, substantial operating time, and use of  stereotactic frame  may limit the widespread use of FUS for intracranial drug delivery. Treatment protocols and dosing schedules for many therapeutic  molecules  still need to be better understood to ensure off-target toxicities are limited. Finally, many studies investigating FUS for intracranial drug delivery use animals with healthy BBBs, but several neurological  diseases  break down the BBB, so current animal  models  may not be very representative.


Despite the limitations, FUS is a promising tool for improving the treatment of many disorders. FUS is currently being studied to facilitate intracranial  gene  delivery for the treatment of Alzheimer's disease. [ 49 ]  A similar approach is also being studied for Parkinson's disease. [ 50 ]  The ability to disrupt the BBB could also allow for delivery of therapeutics to the  motor cortex  to treat  amyotrophic lateral sclerosis . [ 51 ]  There may also be applications of FUS for both  neuromodulation  and targeted drug delivery in  epilepsy ,  Alzheimer's disease ,  Parkinson's disease , depression, and  traumatic brain injury . In the future, research efforts will focus on addressing the challenges and limitations of FUS to develop safe and effective therapies for the most challenging brain conditions.


The  gastrointestinal tract  ( GI tract ,  digestive tract ,  alimentary canal ) is the tract or passageway of the  digestive system  that leads from the  mouth  to the  anus . The GI tract contains all the major  organs  of the digestive system, in humans and other animals, including the  esophagus ,  stomach , and  intestines . Food taken in through the mouth is  digested  to extract  nutrients  and absorb  energy , and the waste expelled at the anus as  feces .  Gastrointestinal  is an adjective meaning of or pertaining to the stomach and intestines.


Most animals  have a "through-gut" or complete digestive tract. Exceptions are more primitive ones:  sponges  have small pores ( ostia ) throughout their body for digestion and a larger dorsal pore ( osculum ) for excretion,  comb jellies  have both a ventral mouth and dorsal anal pores, while  cnidarians  and  acoels  have a single pore for both digestion and excretion. [ 1 ] [ 2 ]


The human gastrointestinal tract consists of the  esophagus ,  stomach, and intestines, and is divided into the upper and lower gastrointestinal tracts. [ 3 ]  The GI tract includes all structures between the  mouth  and the  anus , [ 4 ]  forming a continuous passageway that includes the main organs of digestion, namely, the  stomach ,  small intestine , and  large intestine . The complete  human digestive system  is made up of the gastrointestinal tract plus the accessory organs of digestion (the  tongue ,  salivary glands ,  pancreas ,  liver  and  gallbladder ). [ 5 ]  The tract may also be divided into  foregut ,  midgut , and  hindgut , reflecting the  embryological  origin of each segment. The whole human GI tract is about nine meters (30 feet) long at  autopsy . It is considerably shorter in the living body because the intestines, which are tubes of  smooth muscle tissue , maintain constant  muscle tone  in a halfway-tense state but can relax in spots to allow for local distention and  peristalsis . [ 6 ] [ 7 ]


The gastrointestinal tract contains the  gut microbiota , with some 1,000 different  strains  of  bacteria  having diverse roles in the maintenance of  immune health  and  metabolism , and many other  microorganisms . [ 8 ] [ 9 ] [ 10 ]  Cells of the GI tract release  hormones  to help regulate the digestive process. These  digestive hormones , including  gastrin ,  secretin ,  cholecystokinin , and  ghrelin , are mediated through either  intracrine  or  autocrine  mechanisms, indicating that the cells releasing these hormones are conserved structures throughout  evolution . [ 11 ]


The structure and function can be described both as  gross anatomy  and as  microscopic anatomy  or  histology . The tract itself is divided into upper and lower tracts, and the intestines  small  and  large  parts. [ 12 ]


The upper gastrointestinal tract consists of the  mouth ,  pharynx ,  esophagus ,  stomach , and  duodenum . [ 13 ]
The exact demarcation between the upper and lower tracts is the  suspensory muscle of the duodenum . This differentiates the embryonic borders between the foregut and midgut, and is also the division commonly used by clinicians to describe  gastrointestinal bleeding  as being of either "upper" or "lower" origin. Upon  dissection , the duodenum may appear to be a unified organ, but it is divided into four segments based on function, location, and internal anatomy. The four segments of the duodenum are as follows (starting at the stomach, and moving toward the jejunum):  bulb , descending, horizontal, and ascending. The suspensory muscle attaches the superior border of the ascending duodenum to the  jejunum .


The suspensory muscle is an important anatomical landmark that shows the formal division between the duodenum and the jejunum, the first and second parts of the small intestine, respectively. [ 14 ]  This is a thin muscle which is derived from the  embryonic   mesoderm .


The lower gastrointestinal tract includes most of the  small intestine  and all of the  large intestine . [ 15 ]  In  human anatomy , the  intestine  ( bowel  or  gut ; Greek:  éntera ) is the segment of the gastrointestinal tract extending from the pyloric sphincter of the  stomach  to the  anus  and as in other mammals, consists of two segments: the  small intestine  and the  large intestine . In humans, the small intestine is further subdivided into the  duodenum ,  jejunum , and  ileum  while the large intestine is subdivided into the  cecum , ascending, transverse, descending, and sigmoid  colon ,  rectum , and  anal canal . [ 16 ] [ 17 ]


The  small intestine  begins at the  duodenum  and is a tubular structure, usually between 6 and 7 m long. [ 18 ]  Its  mucosal  area in an adult human is about 30 m 2  (320 sq ft). [ 19 ]  The combination of the  circular folds , the villi, and the microvilli increases the absorptive area of the mucosa about 600-fold, making a total area of about 250 m 2  (2,700 sq ft) for the entire small intestine. [ 20 ]  Its main function is to absorb the products of digestion (including carbohydrates, proteins, lipids, and vitamins) into the bloodstream. There are three major divisions:


The  large intestine , also called the colon, forms an arch starting at the  cecum  and ending at the  rectum  and  anal canal . It also includes the  appendix , which is attached to the  cecum . Its length is about 1.5 m, and the area of the mucosa in an adult human is about 2 m 2  (22 sq ft). [ 19 ]  Its main function is to absorb water and salts. The colon is further divided into:


The gut is an  endoderm -derived structure. At approximately the sixteenth day of human development, the  embryo  begins to fold  ventrally  (with the embryo's ventral surface becoming  concave ) in two directions: the sides of the embryo fold in on each other and the head and tail fold toward one another. The result is that a piece of the  yolk sac , an  endoderm -lined structure in contact with the  ventral  aspect of the embryo, begins to be pinched off to become the primitive gut. The yolk sac remains connected to the gut tube via the  vitelline duct . Usually, this structure regresses during development; in cases where it does not, it is known as  Meckel's diverticulum .


During  fetal  life, the primitive gut is gradually patterned into three segments:  foregut ,  midgut , and  hindgut . Although these terms are often used in reference to segments of the primitive gut, they are also used regularly to describe regions of the definitive gut as well.


Each segment of the gut is further specified and gives rise to specific gut and gut-related structures in later development. Components derived from the gut proper, including the  stomach  and  colon , develop as swellings or dilatations in the cells of the primitive gut. In contrast, gut-related derivatives — that is, those structures that derive from the primitive gut but are not part of the gut proper, in general, develop as out-pouchings of the primitive gut. The blood vessels supplying these structures remain constant throughout development. [ 21 ]


The gastrointestinal tract has a form of general histology with some differences that reflect the specialization in functional anatomy. [ 22 ]  The GI tract can be divided into four concentric layers in the following order:


The mucosa is the innermost layer of the gastrointestinal tract. The mucosa surrounds the  lumen , or open space within the tube. This layer comes in direct contact with digested food ( chyme ). The mucosa is made up of:


The mucosae are highly specialized in each organ of the gastrointestinal tract to deal with the different conditions. The most variation is seen in the epithelium.


The submucosa consists of a dense irregular layer of connective tissue with large blood vessels, lymphatics, and nerves branching into the mucosa and  muscularis externa . It contains the  submucosal plexus , an  enteric nervous plexus , situated on the inner surface of the  muscularis externa .


The  muscular layer  consists of an inner circular layer and a  longitudinal  outer layer. The circular layer prevents food from traveling backward and the longitudinal layer shortens the tract. The layers are not truly longitudinal or circular, rather the layers of muscle are helical with different pitches. The inner circular is helical with a steep pitch and the outer longitudinal is helical with a much shallower pitch. [ 23 ]  Whilst the muscularis externa is similar throughout the entire gastrointestinal tract, an exception is the stomach which has an additional inner oblique muscular layer to aid with grinding and mixing of food. The muscularis externa of the stomach is composed of the inner oblique layer, middle circular layer, and the outer longitudinal layer.


Between the circular and longitudinal muscle layers is the  myenteric plexus . This controls peristalsis. Activity is initiated by the pacemaker cells, (myenteric  interstitial cells of Cajal ). The gut has intrinsic peristaltic activity ( basal electrical rhythm ) due to its self-contained enteric nervous system. The rate can be modulated by the rest of the  autonomic nervous system . [ 23 ]


The coordinated contractions of these layers is called  peristalsis  and propels the food through the tract. Food in the GI tract is called a bolus (ball of food) from the mouth down to the stomach. After the stomach, the food is partially digested and semi-liquid, and is referred to as  chyme . In the large intestine, the remaining semi-solid substance is referred to as  faeces . [ 23 ]


The outermost layer of the gastrointestinal tract consists of several layers of  connective tissue .


Intraperitoneal  parts of the GI tract are covered with  serosa . These include most of the  stomach , first part of the  duodenum , all of the  small intestine ,  caecum  and  appendix ,  transverse colon ,  sigmoid colon  and  rectum . In these sections of the gut, there is a clear boundary between the gut and the surrounding tissue. These parts of the tract have a  mesentery .


Retroperitoneal  parts are covered with  adventitia . They blend into the surrounding tissue and are fixed in position. For example, the retroperitoneal section of the duodenum usually passes through the  transpyloric plane . These include the  esophagus ,  pylorus  of the stomach, distal  duodenum ,  ascending colon ,  descending colon  and  anal canal . In addition, the  oral cavity  has adventitia.


Approximately 20,000 protein coding genes are expressed in human cells and 75% of these genes are expressed in at least one of the different parts of the digestive organ system. [ 24 ] [ 25 ]  Over 600 of these genes are more specifically expressed in one or more parts of the GI tract and the corresponding proteins have functions related to digestion of food and uptake of nutrients. Examples of specific proteins with such functions are  pepsinogen PGC  and the  lipase LIPF , expressed in  chief cells , and gastric  ATPase ATP4A  and  gastric intrinsic factor GIF , expressed in  parietal cells  of the stomach mucosa. Specific proteins expressed in the stomach and duodenum involved in defence include  mucin  proteins, such as  mucin 6  and  intelectin-1 . [ 26 ]