Route of administration

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Route_of_administration

Oral administration of a liquid.

In pharmacology and toxicology, a route of administration (ROA) is the way by which a drug, fluid, poison, or other substance is introduced into the body.

Routes of administration are generally classified by the location at which the substance is applied. Common examples include oral and intravenous administration. Routes can also be classified based on where the target of action is. Action may be topical (local), enteral (system-wide effect, but delivered through the gastrointestinal tract), or parenteral (systemic action, but is delivered by routes other than the GI tract). Route of administration and dosage form are aspects of drug delivery.

Classification

Routes of administration are usually classified by application location (or exposition).

The route or course the active substance takes from application location to the location where it has its target effect is usually rather a matter of pharmacokinetics (concerning the processes of uptake, distribution, and elimination of drugs). Exceptions include the transdermal or transmucosal routes, which are still commonly referred to as routes of administration.

The location of the target effect of active substances is usually rather a matter of pharmacodynamics (concerning, for example, the physiological effects of drugs). An exception is topical administration, which generally means that both the application location and the effect thereof is local.

Topical administration is sometimes defined as both a local application location and local pharmacodynamic effect, and sometimes merely as a local application location regardless of location of the effects.

By application location

Enteral/gastrointestinal route

Through the gastrointestinal tract is sometimes termed enteral or enteric administration (literally meaning 'through the intestines'). Enteral/enteric administration usually includes oral (through the mouth) and rectal (into the rectum) administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may also occur already in the stomach, and as such gastrointestinal (along the gastrointestinal tract) may be a more fitting term for this route of administration. Furthermore, some application locations often classified as enteral, such as sublingual (under the tongue) and sublabial or buccal (between the cheek and gums/gingiva), are taken up in the proximal part of the gastrointestinal tract without reaching the intestines. Strictly enteral administration (directly into the intestines) can be used for systemic administration, as well as local (sometimes termed topical), such as in a contrast enema, whereby contrast media are infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects.

A medical professional injects medication into a gastric tube.

Many drugs as tablets, capsules, or drops are taken orally. Administration methods directly into the stomach include those by gastric feeding tube or gastrostomy. Substances may also be placed into the small intestines, as with a duodenal feeding tube and enteral nutrition. Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet may either cause irritation in the stomach or else be degraded by stomach acids/enzymes.

Administering medication rectally

The rectal route is an effective route of administration for many medications, especially those used at the end of life. The walls of the rectum absorb many medications quickly and effectively. Medications delivered to the distal one-third of the rectum at least partially avoid the "first pass effect" through the liver, which allows for greater bio-availability of many medications than that of the oral route. Rectal mucosa is highly vascularized tissue that allows for rapid and effective absorption of medications. A suppository is a solid dosage form that fits for rectal administration. In hospice care, a specialized rectal catheter, designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the distal rectum, giving health practitioners a way to leverage the established benefits of rectal administration. The Murphy drip is an example of rectal infusion.

Parenteral route

Needle insertion angles for 4 types of parenteral administration of medication: intramuscular, subcutaneous, intravenous, and intradermal injection.

The parenteral route is any route that is not enteral (par- + enteral).

Parenteral administration can be performed by injection, that is, using a needle (usually a hypodermic needle) and a syringe, or by the insertion of an indwelling catheter.

Locations of application of parenteral administration include:

• Central nervous system:

• Epidural (synonym: peridural) (injection or infusion into the epidural space), e.g. epidural anesthesia.
• Intracerebral (into the cerebrum) administration by direct injection into the brain. Used in experimental research of chemicals and as a treatment for malignancies of the brain. The intracerebral route can also interrupt the blood brain barrier from holding up against subsequent routes.
• Intracerebroventricular (into the cerebral ventricles) administration into the ventricular system of the brain. One use is as a last line of opioid treatment for terminal cancer patients with intractable cancer pain.

A transdermal patch which delivers medication is applied to the skin. The patch is labelled with the time and date of administration as well as the administrator's initials.

A medical professional applies nose drops.

• Epicutaneous (application onto the skin). It can be used both for local effect as in allergy testing and typical local anesthesia, as well as systemic effects when the active substance diffuses through skin in a transdermal route.
• Sublingual and buccal medication administration is a way of giving someone medicine orally (by mouth). Sublingual administration is when medication is placed under the tongue to be absorbed by the body. The word "sublingual" means "under the tongue." Buccal administration involves placement of the drug between the gums and the cheek. These medications can come in the form of tablets, films, or sprays. Many drugs are designed for sublingual administration, including cardiovascular drugs, steroids, barbiturates, opioid analgesics with poor gastrointestinal bioavailability, enzymes and, increasingly, vitamins and minerals.
• Extra-amniotic administration, between the endometrium and fetal membranes.
• Nasal administration (through the nose) can be used for topically acting substances, as well as for insufflation of e.g. decongestant nasal sprays to be taken up along the respiratory tract. Such substances are also called inhalational, e.g. inhalational anesthetics.
• Intra-arterial (into an artery), e.g. vasodilator drugs in the treatment of vasospasm and thrombolytic drugs for treatment of embolism.
• Intra-articular, into a joint space. It is generally performed by joint injection. It is mainly used for symptomatic relief in osteoarthritis.
• Intracardiac (into the heart), e.g. adrenaline during cardiopulmonary resuscitation (no longer commonly performed).
• Intracavernous injection, an injection into the base of the penis.
• Intradermal, (into the skin itself) is used for skin testing some allergens, and also for mantoux test for tuberculosis.
• Intralesional (into a skin lesion), is used for local skin lesions, e.g. acne medication.
• Intramuscular (into a muscle), e.g. many vaccines, antibiotics, and long-term psychoactive agents. Recreationally the colloquial term 'muscling' is used.

Topical ocular administration

• Intraocular, into the eye, e.g., some medications for glaucoma or eye neoplasms.
• Intraosseous infusion (into the bone marrow) is, in effect, an indirect intravenous access because the bone marrow drains directly into the venous system. This route is occasionally used for drugs and fluids in emergency medicine and pediatrics when intravenous access is difficult.
• Intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal dialysis.
• Intrathecal (into the spinal canal) is most commonly used for spinal anesthesia and chemotherapy.
• Intrauterine.
• Intravaginal administration, in the vagina.
• Intravenous (into a vein), e.g. many drugs, total parenteral nutrition.
• Intravesical infusion is into the urinary bladder.
• Intravitreal, through the eye.
• Subcutaneous (under the skin). This generally takes the form of subcutaneous injection, e.g. with insulin. Skin popping is a slang term that includes subcutaneous injection, and is usually used in association with recreational drugs. In addition to injection, it is also possible to slowly infuse fluids subcutaneously in the form of hypodermoclysis.
• Transdermal (diffusion through the intact skin for systemic rather than topical distribution), e.g. transdermal patches such as fentanyl in pain therapy, nicotine patches for treatment of addiction and nitroglycerine for treatment of angina pectoris.
• Perivascular administration (perivascular medical devices and perivascular drug delivery systems are conceived for local application around a blood vessel during open vascular surgery).
• Transmucosal (diffusion through a mucous membrane), e.g. insufflation (snorting) of cocaine, sublingual, i.e. under the tongue, sublabial, i.e. between the lips and gingiva, and oral spray or vaginal suppository for nitroglycerine.

Topical route

Main article: Topical drug delivery

The definition of the topical route of administration sometimes states that both the application location and the pharmacodynamic effect thereof is local.

In other cases, topical is defined as applied to a localized area of the body or to the surface of a body part regardless of the location of the effect. By this definition, topical administration also includes transdermal application, where the substance is administered onto the skin but is absorbed into the body to attain systemic distribution.

If defined strictly as having local effect, the topical route of administration can also include enteral administration of medications that are poorly absorbable by the gastrointestinal tract. One such medication is the antibiotic vancomycin, which cannot be absorbed in the gastrointestinal tract and is used orally only as a treatment for Clostridioides difficile colitis.

Choice of routes

The choice of routes of drug administration is governed by various factors:

• Physical and chemical properties of the drug. The physical properties are solid, liquid and gas. The chemical properties are solubility, stability, pH, irritancy, etc.
• Site of desired action: the action may be localised and approachable or generalised and not approachable.
• Rate of extent of absorption of the drug from different routes.
• Effect of digestive juices and the first pass metabolism of drugs.
• Condition of the patient.

In acute situations, in emergency medicine and intensive care medicine, drugs are most often given intravenously. This is the most reliable route, as in acutely ill patients the absorption of substances from the tissues and from the digestive tract can often be unpredictable due to altered blood flow or bowel motility.

Convenience

Enteral routes are generally the most convenient for the patient, as no punctures or sterile procedures are necessary. Enteral medications are therefore often preferred in the treatment of chronic disease. However, some drugs can not be used enterally because their absorption in the digestive tract is low or unpredictable. Transdermal administration is a comfortable alternative; there are, however, only a few drug preparations that are suitable for transdermal administration.

Desired target effect

Identical drugs can produce different results depending on the route of administration. For example, some drugs are not significantly absorbed into the bloodstream from the gastrointestinal tract and their action after enteral administration is therefore different from that after parenteral administration. This can be illustrated by the action of naloxone (Narcan), an antagonist of opiates such as morphine. Naloxone counteracts opiate action in the central nervous system when given intravenously and is therefore used in the treatment of opiate overdose. The same drug, when swallowed, acts exclusively on the bowels; it is here used to treat constipation under opiate pain therapy and does not affect the pain-reducing effect of the opiate.

Oral

The oral route is generally the most convenient and costs the least. However, some drugs can cause gastrointestinal tract irritation. For drugs that come in delayed release or time-release formulations, breaking the tablets or capsules can lead to more rapid delivery of the drug than intended. The oral route is limited to formulations containing small molecules only while biopharmaceuticals (usually proteins) would be digested in the stomach and thereby become ineffective. Biopharmaceuticals have to be given by injection or infusion. However, recent research found various ways to improve oral bioavailability of these drugs. In particular permeation enhancers, ionic liquids, lipid-based nanocarriers, enzyme inhibitors and microneedles have shown potential.

Oral administration is often denoted as "PO" from "per os", the Latin word for "by mouth".

The bioavailability of oral administration is affected by the amount of drug that is absorbed across the intestinal epithelium and first-pass metabolism.

Oral mucosal

The oral mucosa is the mucous membrane lining the inside of the mouth.

Buccal

Buccally administered medication is achieved by placing the drug between gums and the inner lining of the cheek. In comparison with sublingual tissue, buccal tissue is less permeable resulting in slower absorption.

Sublabial

Sublabial administration is achieved by placing the drug between the lip and gum. The frenulum of the tongue may be irritated when in contact with corrosive materials but can be avoided with this route. It is usually used for medications such as nitroglycerin, for example.

Sublingual

Sublingual administration is fulfilled by placing the drug between the tongue and the lower surface of the mouth. The sublingual mucosa is highly permeable and thereby provides access to the underlying expansive network composed of capillaries, leading to rapid drug absorption.

Supralingual

Supralingual administration is achieved by placing the drug above the tongue. It is often the route of administration of choice when one would like the drug to bypass or alleviate the first pass effect on the drug after oral delivery.

Intranasal

Main article: Nasal administration

Drug administration via the nasal cavity yields rapid drug absorption and therapeutic effects. This is because drug absorption through the nasal passages does not go through the gut before entering capillaries situated at tissue cells and then systemic circulation and such absorption route allows transport of drugs into the central nervous system via the pathways of olfactory and trigeminal nerve.

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.

Involved subjects' positions.

Local

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

Skin absorption (dermal absorption), for example, is to directly deliver drug to the skin and, hopefully, to the systemic circulation. However, skin irritation may result, and for some forms such as creams or lotions, the dosage is difficult to control. 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.

Parenteral

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.

A peripheral IV placed on the hand.

A medical professional performs an intradermal (ID) injection.

The term injection encompasses intravenous (IV), intramuscular (IM), subcutaneous (SC or SQ) and intradermal (ID) administration.

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. They also have essentially 100% bioavailability and can be used for drugs that are poorly absorbed or ineffective when they are given orally. Some medications, such as certain antipsychotics, can be administered as long-acting intramuscular injections. Ongoing IV infusions can be used to deliver continuous medication or fluids.

Disadvantages of injections include potential pain or discomfort for the patient and the requirement of trained staff using aseptic techniques for administration. 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.

Respiratory tract

Mouth inhalation

A dummy wears a nebulizer mask, used to administer inhaled medications.

1. trachea (conducting zone)
2. main bronchus (conducting zone)
3. lobar bronchus (conducting zone)
4. segmental bronchus (conducting zone)
5. subsegmental bronchus (conducting zone)
6. conducting bronchiole (conducting zone)
7. terminal bronchiole (conducting zone)
8. respiratory bronchiole (transitional respiratory zone)
9. alveolar duct (transitional respiratory zone)
10. alveolar sac (transitional respiratory zone)
11. alveolus (transitional respiratory zone)

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

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

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

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.

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.

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. 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.

Further information: PM 2.5 and PM 10

Nasal inhalation

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.

Research

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.

Lipid-based nanoparticle

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Lipid-based_nanoparticle 

See also: RNA vaccine and DNA vaccine

Solid lipid nanoparticles (SLNs). There is only one phospholipid layer because the bulk of the interior of the particle is composed of lipophilic substance. Payloads such as modRNA, RNA vaccine or others can be embedded in the interior, as desired. Optionally, targeting-molecules such as antibodies, cell-targeting peptides, and/or other drug molecules can be bound to the exterior surface of the SLN.

Liposomes are ("hollow") lipid nanoparticles which have a phospholipid bilayer as coat, because the bulk of the interior of the particle is composed of aqueous substance. In various popular uses, the optional payload is e.g. DNA vaccines, Gene therapy, vitamins, antibiotics, cosmetics and many others.

Part of a series of articles on https://en.wikipedia.org/wiki/Nanomaterials
Nanomaterials

Lipid-based nanoparticles are very small spherical particles composed of lipids. They are a novel pharmaceutical drug delivery system (part of nanoparticle drug delivery), and a novel pharmaceutical formulation. There are many subclasses of lipid-based nanoparticles such as: lipid nanoparticles (LNPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs).

Sometimes the term "LNP" describes all lipid-based nanoparticles. In specific applications, LNPs describe a specific type of lipid-based nanoparticle, such as the LNPs used for the mRNA vaccine.

Using LNPs for drug delivery was first approved in 2018 for the siRNA drug Onpattro. LNPs became more widely known late in 2020, as some COVID-19 vaccines that use RNA vaccine technology coat the fragile mRNA strands with PEGylated lipid nanoparticles as their delivery vehicle (including both the Moderna and the Pfizer–BioNTech COVID-19 vaccines).

Characteristics

A lipid nanoparticle is typically spherical with an average diameter between 10 and 1000 nanometers. LNPs are made up of phospholipids, cholesterols, ionizable lipids, and polyethylene glycol-derived lipids (PEGylated lipids). Each of these components play a key role in LNPs used for mRNA vaccines that target SARS-CoV-2 (the virus that causes COVID-19). The ionizable cationic lipids bind to mRNA, PEGylated lipids stabilize LNPs, and phospholipids and cholesterol give LNPs their structure. Because of rapid clearance by the immune system of the positively charged lipid, neutral ionizable amino lipids were developed. A novel squaramide lipid (a partially aromatic four-membered ring that can participate in pi–pi interactions) has been used as part of the delivery system used, for example, by Moderna.

Solid lipid nanoparticles (SLNs) possess a solid lipid core matrix that solubilizes lipophilic molecules. Surfactants (emulsifiers) stabilize the lipid core. The emulsifier used depends on administration routes, and is more limited for parenteral administrations. The term "lipid" refers to a broader class of molecules, and includes triglycerides (e.g. tristearin), diglycerides (e.g. glycerol bahenate), monoglycerides (e.g. glycerol monostearate), fatty acids (e.g. stearic acid), steroids (e.g. cholesterol), and waxes (e.g. cetyl palmitate). All classes of emulsifiers (with respect to charge and molecular weight) have been used to stabilize the lipid dispersion. It has been found that the combination of emulsifiers might prevent particle agglomeration more efficiently.

An SLN is generally spherical and consists of a solid lipid core stabilized by a surfactant. The core lipids can be fatty acids, acylglycerols, waxes, and mixtures of these surfactants. Biological membrane lipids, such as phospholipids, sphingomyelins, bile salts (sodium taurocholate), and sterols (cholesterol) are used as stabilizers. Biological lipids having minimum carrier cytotoxicity and the solid state of the lipid permit better controlled drug release due to increased mass transfer resistance.

Structure of NLCs, SLNs, and LNPs

Nanostructured lipid carriers (NLCs) are lipid-based nanoparticles that contain a mixture of solid and liquid lipids in the central core of the lipid carrier. NLCs are derived from SLNs by injecting liquid lipids into the solid core, resulting in a non-uniform internal core. This modification allows for higher drug capacity and more controlled drug delivery.

Preparation

Lipid-based nanoparticles are generally prepared by formulation and self-assembly processes rather than by chemical synthesis of the final particle. Common preparation methods include homogenisation, ultrasonication, solvent emulsification and evaporation, microemulsion-based methods, ethanol injection, and controlled mixing of lipid-containing organic phases with aqueous phases.

Microfluidic and other continuous-flow mixing methods are widely used for lipid nanoparticle and lipid-based nanomedicine preparation because they allow controlled mixing, continuous production, high-throughput formulation screening and improved control of particle size, polydispersity and reproducibility. In these methods, formulation composition, solvent conditions, lipid concentration, flow-rate ratio, total flow rate, temperature and downstream processing can strongly affect the final nanoparticle population.

Applications

Development of solid lipid nanoparticles is one of the fields of lipid nanotechnology (for a review on lipid nanotechnology, see ) with several potential applications in drug delivery, clinical medicine and research, as well as in other disciplines. Due to their size-dependent properties, lipid nanoparticles can possibly develop new therapeutics. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could hold great promise for attaining bioavailability enhancement along with controlled and site-specific drug delivery. SLNs are also considered to be well tolerated in general, due to their composition from physiologically similar lipids.

The conventional approaches such as use of permeation enhancers, surface modification, prodrug synthesis, complex formation and colloidal lipid carrier-based strategies have been developed for the delivery of drugs to intestinal lymphatics. In addition, polymeric nanoparticles, self-emulsifying delivery systems, liposomes, microemulsions, micellar solutions and recently, solid lipid nanoparticles (SLN) have been exploited as probable possibilities as carriers for oral intestinal lymphatic delivery.

Drug delivery

Solid lipid nanoparticles can function as the basis for oral and parenteral drug delivery systems. SLNs combine the advantages of lipid emulsion and polymeric nanoparticle systems while overcoming the temporal and in vivo stability issues that troubles the conventional as well as polymeric nanoparticles drug delivery approaches. It has been proposed that SLNs have many advantages over other colloidal carriers i.e. incorporation of lipophilic and hydrophilic drugs feasible, no biotoxicity of the carrier, avoidance of organic solvents, possibility of controlled drug release and drug targeting, increased drug stability and no problems with respect to large scale production. Various functions such as molecules for targeting, PEG chains for stealth properties, or thiol groups for adhesion via disulfide bond formation can be immobilized on their surface. A recent study has demonstrated the use of solid lipid nanoparticles as a platform for oral delivery of the nutrient mineral iron, by incorporating the hydrophilic molecule ferrous sulfate (FeSO₄) in a lipid matrix composed of stearic acid. Carvedilol-loaded solid lipid nanoparticles were prepared using hot-homogenization technique for oral delivery with compritol and poloxamer 188 as the lipid and surfactant, respectively. Another example of drug delivery using SLN would be oral solid SLN suspended in distilled water, which was synthesized to trap drugs within the SLN structure. Upon ingestion, the SLNs are exposed to gastric and intestinal acids that dissolve the SLNs and release the drugs into the system.

Many nano-structured systems have been employed for ocular drug delivery. SLNs have been looked at as a potential drug carrier system since the 1990s. SLNs do not show biotoxicity as they are prepared from physiological lipids. SLNs are useful in ocular drug delivery as they can enhance the corneal absorption of drugs and improve the ocular bioavailability of both hydrophilic and lipophilic drugs. SLNs have another advantage of allowing autoclave sterilization, a necessary step towards formulation of ocular preparations.

Advantages of SLNs include the use of physiological lipids (which decreases the danger of acute and chronic toxicity), the avoidance of organic solvents, a potential wide application spectrum (dermal, per os, intravenous) and the high pressure homogenization as an established production method. Additionally, improved bioavailability, protection of sensitive drug molecules from the outer environment (e.g. water, light), and even controlled release characteristics were claimed by the incorporation of poorly water-soluble drugs in the solid lipid matrix. Moreover, SLNs can carry both lipophilic and hydrophilic drugs, and are more affordable compared to polymeric/surfactant-based carriers.

Nucleic acids

A significant obstacle to using LNPs as a delivery vehicle for nucleic acids is that in nature, lipids and nucleic acids both carry a negative electric charge—meaning they do not easily mix with each other. While working at Syntex in the mid-1980s, Philip Felgner pioneered the use of artificially-created cationic lipids (positively-charged lipids) to bind lipids to nucleic acids in order to transfect the latter into cells. However, by the late 1990s, it was known from in vitro experiments that this use of cationic lipids had undesired side effects on cell membranes.

During the late 1990s and 2000s, Pieter Cullis, while at the University of British Columbia, developed ionizable cationic lipids which are "positively charged at an acidic pH but neutral in the blood." Cullis also led the development of a technique involving careful adjustments to pH during the process of mixing ingredients in order to create LNPs which could safely pass through the cell membranes of living organisms. As of 2021, the current understanding of LNPs formulated with such ionizable cationic lipids is that they enter cells through receptor-mediated endocytosis and end up inside endosomes. The acidity inside the endosomes causes LNPs' ionizable cationic lipids to acquire a positive charge, and this is thought to allow LNPs to escape from endosomes and release their RNA payloads.

From 2005 into the early 2010s, LNPs were investigated as a drug delivery system for small interfering RNA (siRNA) drugs. In 2009, Cullis co-founded a company called Acuitas Therapeutics to commercialize his LNP research; Acuitas worked on developing LNPs for Alnylam Pharmaceuticals's siRNA drugs. In 2018, the FDA approved Alnylam's siRNA drug Onpattro (patisiran), the first drug to use LNPs as the drug delivery system.

By that point in time, siRNA drug developers like Alnylam were already looking at other options for future drugs like chemical conjugate systems, but during the 2010s, the earlier research into using LNPs for siRNA became a foundation for new research into using LNPs for mRNA. Lipids intended for short siRNA strands did not work well for much longer mRNA strands, which led to extensive research during the mid-2010s into the creation of novel ionizable cationic lipids appropriate for mRNA. As of late 2020, several mRNA vaccines for SARS-CoV-2 use LNPs as their drug delivery system, including both the Moderna COVID-19 vaccine and the Pfizer–BioNTech COVID-19 vaccines. Moderna uses its own proprietary ionizable cationic lipid called SM-102, while Pfizer and BioNTech licensed an ionizable cationic lipid called ALC-0315 from Acuitas.

Lymphatic absorption mechanism

Elucidation of intestinal lymphatic absorption mechanism from solid lipid nanoparticles using Caco-2 cell line as in vitro model was developed. Several researchers have shown the enhancement of oral bioavailibility of poorly water-soluble drugs when encapsulated in solid lipid nanoparticle. This enhanced bioavailibility is achieved via lymphatic delivery. To elucidate the absorption mechanism, from solid lipid nanoparticle, human excised Caco-2 cell monolayer could be alternative tissue for development of an in-vitro model to be used as a screening tool before animal studies are undertaken. The results obtained in this model suggested that the main absorption mechanism of carvedilol loaded solid lipid nanoparticle could be endocytosis and, more specifically, clathrin-mediated endocytosis.

Lipid

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Lipid

Structures of some common lipids. At the top are cholesterol and oleic acid. The middle structure is a triglyceride composed of oleoyl, stearoyl, and palmitoyl chains attached to a glycerol backbone. At the bottom is the common phospholipid phosphatidylcholine.

Lipids are a broad group of organic compounds that include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries, and in nanotechnology.

Lipids are broadly defined as hydrophobic or amphiphilic small molecules; the amphiphilic nature of some lipids allows them to form structures such as vesicles, multilamellar/unilamellar liposomes, or membranes in an aqueous environment. Biological lipids originate entirely or in part from two distinct types of biochemical subunits or "building-blocks": ketoacyl and isoprene groups. Using this approach, lipids may be divided into eight categories: fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).

Although the term lipid is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides. Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, and monoglycerides, and phospholipids), as well as other sterol-containing metabolites such as cholesterol. Although humans and other mammals use various biosynthetic pathways both to break down and to synthesize lipids, some essential lipids cannot be made this way and must be obtained from the diet.

History

In 1815, Henri Braconnot classified lipids (graisses) into two categories, suifs (solid greases or tallow) and huiles (fluid oils). In 1823, Michel Eugène Chevreul developed a more detailed classification, including oils, greases, tallow, waxes, resins, balsams and volatile oils (or essential oils). In 1827, William Prout recognized fat ("oily" alimentary matters), along with protein ("albuminous") and carbohydrate ("saccharine"), as an important nutrient for humans and animals.

The first synthetic triglyceride was reported by Théophile-Jules Pelouze in 1844, when he produced tributyrin by treating butyric acid with glycerin in the presence of concentrated sulfuric acid. Several years later, Marcellin Berthelot, one of Pelouze's students, synthesized tristearin and tripalmitin by reaction of the analogous fatty acids with glycerin in the presence of gaseous hydrogen chloride at high temperature.

For a century, chemists regarded "fats" as only simple lipids made of fatty acids and glycerol (glycerides), but new forms were described later. Theodore Gobley (1847) discovered phospholipids in mammalian brain and hen egg, called by him as "lecithins". Thudichum discovered in the human brain some phospholipids (cephalin), glycolipids (cerebroside) and sphingolipids (sphingomyelin).

The terms lipoid, lipin, lipide and lipid have been used with varied meanings from author to author. In 1912, Rosenbloom and Gies proposed the substitution of "lipoid" by "lipin". In 1920, Bloor introduced a new classification for "lipoids": simple lipoids (greases and waxes), compound lipoids (phospholipoids and glycolipoids), and the derived lipoids (fatty acids, alcohols, sterols).

The word lipide, which stems etymologically from Greek λίπος, lipos 'fat', was introduced in 1923 by the French pharmacologist Gabriel Bertrand. Bertrand included in the concept not only the traditional fats (glycerides), but also the "lipoids", with a complex constitution. The word lipide was unanimously approved by the international commission of the Société de Chimie Biologique during the plenary session on July 3, 1923. The word lipide was later anglicized as lipid because of its pronunciation ('lɪpɪd). In French, the suffix -ide, from Ancient Greek -ίδης (meaning 'son of' or 'descendant of'), is always pronounced (ɪd).

In 1947, T. P. Hilditch defined "simple lipids" as greases and waxes (true waxes, sterols, alcohols).

Categories

Lipids have been classified into eight categories by the Lipid MAPS consortium as follows:

Fatty acids

Main article: Fatty acid

I₂ – Prostacyclin (an example of a prostaglandin, an eicosanoid fatty acid)

LTB₄ (an example of a leukotriene, an eicosanoid fatty acid)

Fatty acyls, a generic term for describing fatty acids, their conjugates and derivatives, are a diverse group of molecules synthesized by chain-elongation of an acetyl-CoA primer with malonyl-CoA or methylmalonyl-CoA groups in a process called fatty acid synthesis. They are made of a hydrocarbon chain that terminates with a carboxylic acid group; this arrangement confers the molecule with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in water. The fatty acid structure is one of the most fundamental categories of biological lipids and is commonly used as a building-block of more structurally complex lipids. The carbon chain, typically between four and 24 carbons long, may be saturated or unsaturated, and may be attached to functional groups containing oxygen, halogens, nitrogen, and sulfur. If a fatty acid contains a double bond, there is the possibility of either a cis or trans geometric isomerism, which significantly affects the molecule's configuration. Cis-double bonds cause the fatty acid chain to bend, an effect that is compounded with more double bonds in the chain. Three double bonds in 18-carbon linolenic acid, the most abundant fatty-acyl chains of plant thylakoid membranes, render these membranes highly fluid despite environmental low-temperatures, and also makes linolenic acid give dominating sharp peaks in high resolution 13-C NMR spectra of chloroplasts. This in turn plays an important role in the structure and function of cell membranes. Most naturally occurring fatty acids are of the cis configuration, although the trans form does exist in some natural and partially hydrogenated fats and oils.

Examples of biologically important fatty acids include the eicosanoids, derived primarily from arachidonic acid and eicosapentaenoic acid, that include prostaglandins, leukotrienes, and thromboxanes. Docosahexaenoic acid is also important in biological systems, particularly with respect to sight. Other major lipid classes in the fatty acid category are the fatty esters and fatty amides. Fatty esters include important biochemical intermediates such as wax esters, fatty acid thioester coenzyme A derivatives, fatty acid thioester ACP derivatives and fatty acid carnitines. The fatty amides include N-acyl ethanolamines, such as the cannabinoid neurotransmitter anandamide.

Glycerolipids

Example of an unsaturated fat triglyceride (C₅₅H₉₈O₆). Left part: glycerol; right part, from top to bottom: palmitic acid, oleic acid, alpha-linolenic acid.

Glycerolipids are composed of mono-, di-, and tri-substituted glycerols, the best-known being the fatty acid triesters of glycerol, called triglycerides. The word "triacylglycerol" is sometimes used synonymously with "triglyceride". In these compounds, the three hydroxyl groups of glycerol are each esterified, typically by different fatty acids. Because they function as an energy store, these lipids comprise the bulk of storage fat in animal tissues. The hydrolysis of the ester bonds of triglycerides and the release of glycerol and fatty acids from adipose tissue are the initial steps in metabolizing fat.

Additional subclasses of glycerolipids are represented by glycosylglycerols, which are characterized by the presence of one or more sugar residues attached to glycerol via a glycosidic linkage. Examples of structures in this category are the digalactosyldiacylglycerols found in plant membranes and seminolipid from mammalian sperm cells.

Glycerophospholipids

Main article: Glycerophospholipid

Phosphatidylethanolamine

Glycerophospholipids, usually referred to as phospholipids (though sphingomyelins are also classified as phospholipids), are ubiquitous in nature and are key components of the lipid bilayer of cells, as well as being involved in metabolism and cell signaling. Neural tissue (including the brain) contains relatively high amounts of glycerophospholipids, and alterations in their composition has been implicated in various neurological disorders. Glycerophospholipids may be subdivided into distinct classes, based on the nature of the polar headgroup at the sn-3 position of the glycerol backbone in eukaryotes and eubacteria, or the sn-1 position in the case of archaebacteria.

Examples of glycerophospholipids found in biological membranes are phosphatidylcholine (also known as PC, GPCho or lecithin), phosphatidylethanolamine (PE or GPEtn) and phosphatidylserine (PS or GPSer). In addition to serving as a primary component of cellular membranes and binding sites for intra- and intercellular proteins, some glycerophospholipids in eukaryotic cells, such as phosphatidylinositols and phosphatidic acids are either precursors of or, themselves, membrane-derived second messengers. Typically, one or both of these hydroxyl groups are acylated with long-chain fatty acids, but there are also alkyl-linked and 1Z-alkenyl-linked (plasmalogen) glycerophospholipids, as well as dialkylether variants in archaebacteria.

Sphingolipids

Main article: Sphingolipid

Sphingomyelin

Sphingolipids are a complicated family of compounds that share a common structural feature, a sphingoid base backbone that is synthesized de novo from the amino acid serine and a long-chain fatty acyl CoA, then converted into ceramides, phosphosphingolipids, glycosphingolipids and other compounds. The major sphingoid base of mammals is commonly referred to as sphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of sphingoid base derivatives with an amide-linked fatty acid. The fatty acids are typically saturated or mono-unsaturated with chain lengths from 16 to 26 carbon atoms.

The major phosphosphingolipids of mammals are sphingomyelins (ceramide phosphocholines), whereas insects contain mainly ceramide phosphoethanolamines and fungi have phytoceramide phosphoinositols and mannose-containing headgroups. The glycosphingolipids are a diverse family of molecules composed of one or more sugar residues linked via a glycosidic bond to the sphingoid base. Examples of these are the simple and complex glycosphingolipids such as cerebrosides and gangliosides.

Sterols

Chemical structure of cholesterol

Main article: Sterol

Sterols, such as cholesterol and its derivatives, are an important component of membrane lipids, along with the glycerophospholipids and sphingomyelins. Other examples of sterols are the bile acids and their conjugates, which in mammals are oxidized derivatives of cholesterol and are synthesized in the liver. The plant equivalents are the phytosterols, such as β-sitosterol, stigmasterol, and brassicasterol; the latter compound is also used as a biomarker for algal growth. The predominant sterol in fungal cell membranes is ergosterol.

Sterols are steroids in which one of the hydrogen atoms is substituted with a hydroxyl group, at position 3 in the carbon chain. They have in common with steroids the same fused four-ring core structure. Steroids have different biological roles as hormones and signaling molecules. The eighteen-carbon (C18) steroids include the estrogen family whereas the C19 steroids comprise the androgens such as testosterone and androsterone. The C21 subclass includes the progestogens as well as the glucocorticoids and mineralocorticoids. The secosteroids, comprising various forms of vitamin D, are characterized by cleavage of the B ring of the core structure.

Prenols

Prenol lipid (2E-geraniol)

Prenol lipids are synthesized from the five-carbon-unit precursors isopentenyl diphosphate and dimethylallyl diphosphate, which are produced mainly via the mevalonic acid (MVA) pathway. The simple isoprenoids (linear alcohols, diphosphates, etc.) are formed by the successive addition of C5 units, and are classified according to number of these terpene units. Structures containing greater than 40 carbons are known as polyterpenes. Carotenoids are important simple isoprenoids that function as antioxidants and as precursors of vitamin A. Another biologically important class of molecules is exemplified by the quinones and hydroquinones, which contain an isoprenoid tail attached to a quinonoid core of non-isoprenoid origin. Vitamin E and vitamin K, as well as the ubiquinones, are examples of this class. Prokaryotes synthesize polyprenols (called bactoprenols) in which the terminal isoprenoid unit attached to oxygen remains unsaturated, whereas in animal polyprenols (dolichols) the terminal isoprenoid is reduced.

Saccharolipids

Structure of the saccharolipid Kdo₂-lipid A. Glucosamine residues in blue, Kdo residues in red, acyl chains in black and phosphate groups in green.

Saccharolipids describe compounds in which fatty acids are linked to a sugar backbone, forming structures that are compatible with membrane bilayers. In the saccharolipids, a monosaccharide substitutes for the glycerol backbone present in glycerolipids and glycerophospholipids. The most familiar saccharolipids are the acylated glucosamine precursors of the Lipid A component of the lipopolysaccharides in Gram-negative bacteria. Typical lipid A molecules are disaccharides of glucosamine, which are derivatized with as many as seven fatty-acyl chains. The minimal lipopolysaccharide required for growth in E. coli is Kdo₂-Lipid A, a hexa-acylated disaccharide of glucosamine that is glycosylated with two 3-deoxy-D-manno-octulosonic acid (Kdo) residues.

Polyketides

Polyketides are synthesized by polymerization of acetyl and propionyl subunits by classic enzymes as well as iterative and multimodular enzymes that share mechanistic features with the fatty acid synthases. They comprise many secondary metabolites and natural products from animal, plant, bacterial, fungal and marine sources, and have great structural diversity. Many polyketides are cyclic molecules whose backbones are often further modified by glycosylation, methylation, hydroxylation, oxidation, or other processes. Many commonly used antimicrobial, antiparasitic, and anticancer agents are polyketides or polyketide derivatives, such as erythromycins, tetracyclines, avermectins, and antitumor epothilones.

Biological functions

Component of biological membranes

Eukaryotic cells feature the compartmentalized membrane-bound organelles that carry out different biological functions. The glycerophospholipids are the main structural component of biological membranes, as the cellular plasma membrane and the intracellular membranes of organelles; in animal cells, the plasma membrane physically separates the intracellular components from the extracellular environment. The glycerophospholipids are amphipathic molecules (containing both hydrophobic and hydrophilic regions) that contain a glycerol core linked to two fatty acid-derived "tails" by ester linkages and to one "head" group by a phosphate ester linkage. While glycerophospholipids are the major component of biological membranes, other non-glyceride lipid components such as sphingomyelin and sterols (mainly cholesterol in animal cell membranes) are also found in biological membranes. In plants and algae, the galactosyldiacylglycerols, and sulfoquinovosyldiacylglycerol, which lack a phosphate group, are important components of membranes of chloroplasts and related organelles and are among the most abundant lipids in photosynthetic tissues, including those of higher plants, algae and certain bacteria.

Plant thylakoid membranes have the largest lipid component of a non-bilayer forming monogalactosyl diglyceride (MGDG), and little phospholipids; despite this unique lipid composition, chloroplast thylakoid membranes have been shown to contain a dynamic lipid-bilayer matrix as revealed by magnetic resonance and electron microscope studies.

Self-organization of phospholipids: a spherical liposome, a micelle, and a lipid bilayer.

A biological membrane is a form of lamellar phase lipid bilayer. The formation of lipid bilayers is an energetically preferred process when the glycerophospholipids described above are in an aqueous environment. This is known as the hydrophobic effect. In an aqueous system, the polar heads of lipids align towards the polar, aqueous environment, while the hydrophobic tails minimize their contact with water and tend to cluster together, forming a vesicle; depending on the concentration of the lipid, this biophysical interaction may result in the formation of micelles, liposomes, or lipid bilayers. Other aggregations are also observed and form part of the polymorphism of amphiphile (lipid) behavior. Phase behavior is an area of study within biophysics. Micelles and bilayers form in the polar medium by a process known as the hydrophobic effect. When dissolving a lipophilic or amphiphilic substance in a polar environment, the polar molecules (i.e., water in an aqueous solution) become more ordered around the dissolved lipophilic substance, since the polar molecules cannot form hydrogen bonds to the lipophilic areas of the amphiphile. So in an aqueous environment, the water molecules form an ordered "clathrate" cage around the dissolved lipophilic molecule.

The formation of lipids into protocell membranes represents a key step in models of abiogenesis, the origin of life.

Energy storage

Triglycerides, stored in adipose tissue, are a major form of energy storage both in animals and plants. They are a major source of energy in aerobic respiration. The complete oxidation of fatty acids releases about 38 kJ/g (9 kcal/g), compared with only 17 kJ/g (4 kcal/g) for the oxidative breakdown of carbohydrates and proteins. The adipocyte, or fat cell, is designed for continuous synthesis and breakdown of triglycerides in animals, with breakdown controlled mainly by the activation of hormone-sensitive enzyme lipase. Migratory birds that must fly long distances without eating use triglycerides to fuel their flights.

Signaling

Evidence has emerged showing that lipid signaling is a vital part of the cell signaling. Lipid signaling may occur via activation of G protein-coupled or nuclear receptors, and members of several different lipid categories have been identified as signaling molecules and cellular messengers. These include sphingosine-1-phosphate, a sphingolipid derived from ceramide that is a potent messenger molecule involved in regulating calcium mobilization, cell growth, and apoptosis; diacylglycerol and the phosphatidylinositol phosphates (PIPs), involved in calcium-mediated activation of protein kinase C; the prostaglandins, which are one type of fatty-acid derived eicosanoid involved in inflammation and immunity; the steroid hormones such as estrogen, testosterone and cortisol, which modulate a host of functions such as reproduction, metabolism and blood pressure; and the oxysterols such as 25-hydroxy-cholesterol that are liver X receptor agonists. Phosphatidylserine lipids are known to be involved in signaling for the phagocytosis of apoptotic cells or pieces of cells. They accomplish this by being exposed to the extracellular face of the cell membrane after the inactivation of flippases which place them exclusively on the cytosolic side and the activation of scramblases, which scramble the orientation of the phospholipids. After this occurs, other cells recognize the phosphatidylserines and phagocytosize the cells or cell fragments exposing them.

Other functions

The "fat-soluble" vitamins (A, D, E and K) – which are isoprene-based lipids – are essential nutrients stored in the liver and fatty tissues, with a diverse range of functions. Acyl-carnitines are involved in the transport and metabolism of fatty acids in and out of mitochondria, where they undergo beta oxidation. Polyprenols and their phosphorylated derivatives also play important transport roles, in this case the transport of oligosaccharides across membranes. Polyprenol phosphate sugars and polyprenol diphosphate sugars function in extra-cytoplasmic glycosylation reactions, in extracellular polysaccharide biosynthesis (for instance, peptidoglycan polymerization in bacteria), and in eukaryotic protein N-glycosylation. Cardiolipins are a subclass of glycerophospholipids containing four acyl chains and three glycerol groups that are particularly abundant in the inner mitochondrial membrane. They are believed to activate enzymes involved with oxidative phosphorylation. Lipids also form the basis of steroid hormones.

Metabolism

The major dietary lipids for humans and other animals are animal and plant triglycerides, sterols, and membrane phospholipids. The process of lipid metabolism synthesizes and degrades the lipid stores and produces the structural and functional lipids characteristic of individual tissues.

Biosynthesis

See also: Fatty acid synthesis

In animals, when there is an oversupply of dietary carbohydrate, the excess carbohydrate is converted to triglycerides. This involves the synthesis of fatty acids from acetyl-CoA and the esterification of fatty acids in the production of triglycerides, a process called lipogenesis. Fatty acids are made by fatty acid synthases that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the acetyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional protein, while in plant plastids and bacteria separate enzymes perform each step in the pathway. The fatty acids may be subsequently converted to triglycerides that are packaged in lipoproteins and secreted from the liver.

The synthesis of unsaturated fatty acids involves a desaturation reaction, whereby a double bond is introduced into the fatty acyl chain. For example, in humans, the desaturation of stearic acid by stearoyl-CoA desaturase-1 produces oleic acid. The doubly unsaturated fatty acid linoleic acid as well as the triply unsaturated α-linolenic acid cannot be synthesized in mammalian tissues, and are therefore essential fatty acids and must be obtained from the diet.

Triglyceride synthesis takes place in the endoplasmic reticulum by metabolic pathways in which acyl groups in fatty acyl-CoAs are transferred to the hydroxyl groups of glycerol-3-phosphate and diacylglycerol.

Terpenes and isoprenoids, including the carotenoids, are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate. These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA, while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates. One important reaction that uses these activated isoprene donors is steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol. Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.

Degradation

See also: Fatty acid degradation

Beta oxidation is the metabolic process by which fatty acids are broken down in the mitochondria or in peroxisomes to generate acetyl-CoA. For the most part, fatty acids are oxidized by a mechanism that is similar to, but not identical with, a reversal of the process of fatty acid synthesis. That is, two-carbon fragments are removed sequentially from the carboxyl end of the acid after steps of dehydrogenation, hydration, and oxidation to form a beta-keto acid, which is split by thiolysis. The acetyl-CoA is then ultimately converted into adenosine triphosphate (ATP), CO₂, and H₂O using the citric acid cycle and the electron transport chain. Hence the citric acid cycle can start at acetyl-CoA when fat is being broken down for energy if there is little or no glucose available. The energy yield of the complete oxidation of the fatty acid palmitate is 106 ATP. Unsaturated and odd-chain fatty acids require additional enzymatic steps for degradation.

Nutrition and health

Most of the fat found in food is in the form of triglycerides, cholesterol, and phospholipids. Some dietary fat is necessary to facilitate absorption of fat-soluble vitamins (A, D, E, and K) and carotenoids. Humans and other mammals have a dietary requirement for certain essential fatty acids, such as linoleic acid (an omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid) because they cannot be synthesized from simple precursors in the diet. Both of these fatty acids are 18-carbon polyunsaturated fatty acids differing in the number and position of the double bonds. Most vegetable oils are rich in linoleic acid (safflower, sunflower, and corn oils). Alpha-linolenic acid is found in the green leaves of plants and in some seeds, nuts, and legumes (in particular flax, rapeseed, walnut, and soy). Fish oils are particularly rich in the longer-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. Many studies have shown positive health benefits associated with consumption of omega-3 fatty acids on infant development, cancer, cardiovascular diseases, and various mental illnesses (such as depression, attention-deficit hyperactivity disorder, and dementia).

In contrast, it is now well-established that consumption of trans fats, such as those present in partially hydrogenated vegetable oils, are a risk factor for cardiovascular disease. Fats that are good for one may be turned into trans fats by improper cooking methods that result in overcooking the lipids.

Results from recent clinical trials have linked long-term variation in lipids, including LDL and triglycerides, with risk of cardiovascular disease, diabetes, or heart failure. Excessive lipid variability has been linked to oxidative stress and endothelial dysfunction.

A few studies have suggested that total dietary fat intake is linked to an increased risk of obesity and diabetes. Others, including the Women's Health Initiative Dietary Modification Trial, an eight-year study of 49,000 women, the Nurses' Health Study, and the Health Professionals Follow-up Study, revealed no such links. None of these studies suggested any connection between percentage of calories from fat and risk of cancer, heart disease, or weight gain. The Nutrition Source, a website maintained by the department of nutrition at the T. H. Chan School of Public Health at Harvard University, summarizes the current evidence on the effect of dietary fat: "Detailed research—much of it done at Harvard—shows that the total amount of fat in the diet isn't really linked with weight or disease."