Cromoglicic acid (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
)—also referred to as cromolyn (
USAN
280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk(于山國)was Ulleungdo(鬱陵島)
Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...
), cromoglycate (former
BAN), or cromoglicate—is traditionally described as a
mast cell stabilizer
Mast cell stabilizers are medications used to prevent or control certain allergic disorders. They block mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related mediators. One suspected pharmaco ...
, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium. This drug prevents the release of
inflammatory chemicals such as
histamine
Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...
from
mast cell
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s.
Cromoglicic acid has been the non-
corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
treatment of choice in the treatment of
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
, for which it has largely been replaced by
leukotriene receptor antagonist
An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor (arachidonate 5-lipoxygenase) or leukotriene receptor antagonist (cysteinyl leuko ...
s because of their convenience (and perceived safety). Cromoglicic acid requires administration four times daily, and does not provide additive benefit in combination with inhaled corticosteroids.
History
Cromolyn sodium was discovered in 1965 by
Roger Altounyan
Roger Edward Collingwood Altounyan (1922–1987) was an Anglo-Armenian physician and pharmacologist who pioneered the use of sodium cromoglycate as a remedy for asthma. His family relocated to the United Kingdom where he studied medicine and star ...
, a
pharmacologist
Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
who had asthma. It is considered a breakthrough drug in management of asthma, as the patients can be freed from steroids in many cases; however, it is mainly effective as a prophylaxis for allergic and exercise-induced asthma, not as a treatment for acute attacks. Altounyan was investigating certain plants and herbs which have bronchodilating properties. One such plant was
khella
''Visnaga daucoides'' is a species of flowering plant in the carrot family known by many common names, including toothpick-plant, toothpickweed, bisnaga, khella, or sometimes bishop's weed. It is native to Europe, Asia, and North Africa, but it ...
(''Ammi visnaga'') which had been used as a muscle relaxant since ancient times in Egypt. Altounyan deliberately inhaled derivatives of the active ingredient
khellin
Khellin has been used as an herbal folk medicine, with use in the Mediterranean dating back to Ancient Egypt, to treat a variety of maladies including: renal colic, kidney stones, coronary disease, bronchial asthma, vitiligo, and psoriasis. It ...
to determine if they could block his asthma attacks. After several years of trial he isolated an effective and safe asthma-preventing compound called cromolyn sodium.
Preparations
Cromoglicic acid is available in multiple forms:
* as a
nasal spray
Nasal sprays are used to deliver medications locally in the nasal cavities or systemically. They are used locally for conditions such as nasal congestion and allergic rhinitis. In some situations, the nasal delivery route is preferred for syste ...
(Rynacrom (UK), Lomusol (France), Nasalcrom (the only
over-the-counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
form, US), Prevalin (non-direct version, NL)) to treat
allergic rhinitis
Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. Signs and symptoms include a runny or stuffy nose, sneezing, red, i ...
.
* in a nebulizer solution for aerosol administration to treat
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
.
* as an
inhaler
An inhaler (also known as a puffer, pump or allergy spray) is a medical device used for delivering medicines into the lungs through the work of a person's breathing. This allows medicines to be delivered to and absorbed in the lungs, which prov ...
(Intal, Fisons Pharmaceuticals, UK) for preventive management of
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
.
The maker of Intal, King Pharmaceuticals, has discontinued manufacturing the inhaled form, cromolyn sodium inhalation aerosol, due to issues involving CFC-free propellant. As stocks are depleted, this inhaler preparation will no longer be available to patients. In the EU it is manufactured without CFCs by
Sanofi
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
, although it must be imported from Canada or Mexico for USA residents.
* as
eye drop
Eye drops or eyedrops are liquid drops applied directly to the surface of the eye usually in small amounts such as a single drop or a few drops. Eye drops usually contain saline to match the salinity of the eye. Drops containing only saline ...
s (Opticrom and Optrex Allergy (UK), Crolom, Cromolyn (Canada)) for
allergic conjunctivitis
Allergic conjunctivitis (AC) is inflammation of the conjunctiva (the membrane covering the white part of the eye) due to allergy. Although allergens differ among patients, the most common cause is hay fever. Symptoms consist of redness (mainly due ...
* in an oral form (Gastrocrom, Nalcrom) to treat
mastocytosis
Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called ''mastocytes'') and CD34+ mast cell precursors.
People affected by masto ...
,
mast cell activation syndrome
Mast cell activation syndrome (MCAS) is a type of mast cell activation disorder (MCAD), and is an immunological condition in which mast cells inappropriately and excessively release chemical mediators, resulting in a range of chronic symptoms, ...
,
dermatographic urticaria
Dermatographic urticaria is a skin disorder and one of the most common types of urticaria, affecting 2–5% of the population.
Signs and symptoms
The condition manifests as an allergic-like reaction, causing a warm red wheal to appear on the sk ...
and
ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...
. Another oral product, Intercron (sodium cromoglicate in distilled water, from
Zambon
Zambon is an Italian company that has been operating in the pharmaceutical and fine chemical industry since 1906. The company is currently run by Elena Zambon who is the daughter of the founder.{{Cite news, url=http://www.repubblica.it/economia/a ...
France), is used for food allergies.
Mechanism of action
"Cromolyn works because it prevents the release of mediators that would normally attract inflammatory cells and because it stabilizes the inflammatory cells. MCT mast cells found in the mucosa are stabilised."
Nedocromil
Nedocromil sodium is a medication considered as mast cell stabilizer which acts to prevent wheezing, shortness of breath, and other breathing problems caused by asthma. It is administered by an inhaler under the brand name Tilade, and as an eye dro ...
is another mast cell stabilizer that also works in controlling asthma.
The underlying
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
is not fully understood; for while cromoglicate stabilizes mast cells, this mechanism is probably not why it works in asthma.
[H. P. Rang et al., ''Pharmacology'', Fifth Edition. (2003) ] Pharmaceutical companies have produced 20 related compounds that are equally or more potent at stabilising mast cells and none of them have shown any anti-asthmatic effect.
It is more likely that these work by inhibiting the response of sensory
C fibers
Group C nerve fibers are one of three classes of nerve fiber in the central nervous system (CNS) and peripheral nervous system (PNS). The C group fibers are unmyelinated and have a small diameter and low conduction velocity, whereas Groups A ...
to the irritant
capsaicin
Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burning ...
, inhibiting local axon reflexes involved in asthma, and may inhibit the release of preformed T cell cytokines and mediators involved in asthma. (see review by Garland, 1991)
It is known to somewhat inhibit
chloride channels
Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Several ...
(37% ± 7%) and thus ''may'' inhibit the:
* exaggerated neuronal reflexes triggered by stimulation of irritant receptors on sensory nerve endings (e.g. exercise-induced asthma)
* release of preformed
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
from several type of inflammatory cells (
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s,
eosinophils
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
) in allergen-induced asthma
Note: Another chemical (NPPB: 5-nitro-2(3-phenyl) propylamino-benzoic acid) was shown, in the same study, to be a more effective chloride channel blocker.
Finally it may act by inhibiting calcium influx.
Cromoglicate is classified as a
chromone
Chromone (or 1,4-benzopyrone) is a derivative of benzopyran with a substituted keto group on the pyran ring. It is an isomer of coumarin.
Derivatives of chromone are collectively known as ''chromones''. Most, though not all, chromones are also ...
.
Cromolyn is also being tested as a drug to treat
insulin-induced lipoatrophy and
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
in combination with
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...
. Cromolyn is also known to bind S100P protein and disrupt the interaction with
RAGE.
Synthesis
References
External links
{{Asthma and copd rx
Mast cell stabilizers
Enoic acids
Chromones
British inventions
Glycerols
Orphan drugs