Amphotericin B is an
antifungal medication
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypt ...
used for serious
fungal infection
Fungal infection, also known as mycosis, is disease caused by fungi. Different types are traditionally divided according to the part of the body affected; superficial, subcutaneous, and systemic. Superficial fungal infections include common ti ...
s and
leishmaniasis
Leishmaniasis is a wide array of clinical manifestations caused by parasites of the trypanosome genus ''Leishmania''. It is generally spread through the bite of phlebotomine sandflies, ''Phlebotomus'' and ''Lutzomyia'', and occurs most freq ...
.
The fungal infections it is used to treat include
mucormycosis
Mucormycosis, also known as black fungus, is a serious fungal infection that comes under fulminant fungal sinusitis, usually in people who are immunocompromised. It is curable only when diagnosed early. Symptoms depend on where in the body the ...
,
aspergillosis
Aspergillosis is a fungal infection of usually the lungs, caused by the genus ''Aspergillus'', a common mould that is breathed in frequently from the air around, but does not usually affect most people. It generally occurs in people with lung dise ...
,
blastomycosis
Blastomycosis or blasto is a fungal infection caused by inhaling spores of a ''Blastomyces'' fungus. Only about half of people with the disease have symptoms, which can include fever, cough, night sweats, muscle pains, weight loss, chest pain, a ...
,
candidiasis
Candidiasis is a fungal infection due to any type of '' Candida'' (a type of yeast). When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the mouth ...
,
coccidioidomycosis
Coccidioidomycosis (, ), commonly known as cocci, Valley fever, as well as California fever, desert rheumatism, or San Joaquin Valley fever, is a mammalian fungal disease caused by ''Coccidioides immitis'' or ''Coccidioides posadasii''. Coccidio ...
, and
cryptococcosis
Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, difficulty breathing, chest pain and fever are seen when the lungs are infected. When the ...
.
[ For certain infections it is given with ]flucytosine
Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication. It is specifically used, together with amphotericin B, for serious ''Candida'' infections and cryptococcosis. It may be used by itself or with other antifungals for ...
. It is typically given intravenously
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
(injection into a vein).
Common side effects include a reaction with fever
Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
, chills, and headaches
Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches.
Headaches can occur as a result of m ...
soon after the medication is given, as well as kidney problems
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
.[ Allergic symptoms including ]anaphylaxis
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
may occur.[ Other serious side effects include ]low blood potassium
Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnor ...
and myocarditis
Myocarditis, also known as inflammatory cardiomyopathy, is an acquired cardiomyopathy due to inflammation of the heart muscle. Symptoms can include shortness of breath, chest pain, decreased ability to exercise, and an irregular heartbeat. The ...
(inflammation of the heart).[ It appears to be relatively safe in ]pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
.[ There is a lipid formulation that has a lower risk of side effects.][ It is in the ]polyene
In organic chemistry, polyenes are poly- unsaturated, organic compounds that contain at least three alternating double () and single () carbon–carbon bonds. These carbon–carbon double bonds interact in a process known as conjugation, resultin ...
class of medications and works in part by interfering with the cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
of the fungus.[
Amphotericin B was isolated from '' Streptomyces nodosus'' in 1955 at the Squibb For Medical Research Institute from cultures isolated from the ''streptomycete'' obtained from the river bed of ]Orinoco
The Orinoco () is one of the longest rivers in South America at . Its drainage basin, sometimes known as the Orinoquia, covers , with 76.3 percent of it in Venezuela and the remainder in Colombia. It is the fourth largest river in the wor ...
in that region of Venezuela
Venezuela (; ), officially the Bolivarian Republic of Venezuela ( es, link=no, República Bolivariana de Venezuela), is a country on the northern coast of South America, consisting of a continental landmass and many islands and islets in th ...
and came into medical use in 1958. It is on the World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. It is available as a generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
.[
]
Medical uses
Antifungal
One of the main uses of amphotericin B is treating a wide range of systemic fungal infection
Fungal infection, also known as mycosis, is disease caused by fungi. Different types are traditionally divided according to the part of the body affected; superficial, subcutaneous, and systemic. Superficial fungal infections include common ti ...
s. Due to its extensive side effects, it is often reserved for severe infections in critically ill, or immunocompromised
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
patients. It is considered first line therapy for invasive mucormycosis
Mucormycosis, also known as black fungus, is a serious fungal infection that comes under fulminant fungal sinusitis, usually in people who are immunocompromised. It is curable only when diagnosed early. Symptoms depend on where in the body the ...
infections, cryptococcal meningitis
Cryptococcosis is a potentially fatal mycosis, fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, shortness of breath, difficulty breathing, chest pain and fever are seen when the ...
, and certain aspergillus
' () is a genus consisting of several hundred mold species found in various climates worldwide.
''Aspergillus'' was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under a microscope, Miche ...
and candidal infections. It has been a highly effective drug for over fifty years in large part because it has a low incidence of drug resistance in the pathogens it treats. This is because amphotericin B resistance requires sacrifices on the part of the pathogen that make it susceptible to the host environment, and too weak to cause infection.
Antiprotozoal
Amphotericin B is used for life-threatening protozoan infections
Protozoan infections are parasitic diseases caused by organisms formerly classified in the kingdom Protozoa. They are usually contracted by either an insect vector or by contact with an infected substance or surface and include organisms that are ...
such as visceral leishmaniasis
Visceral leishmaniasis (VL), also known as kala-azar (Hindi: kālā āzār, "black sickness") or "black fever", is the most severe form of leishmaniasis and, without proper diagnosis and treatment, is associated with high fatality. Leishmaniasis ...
and primary amoebic meningoencephalitis
Naegleriasis (also known as primary amoebic meningoencephalitis; PAM) is an almost invariably fatal infection of the brain by the free-living unicellular eukaryote ''Naegleria fowleri''. Symptoms are meningitis-like and include headache, fever ...
.
Spectrum of susceptibility
The following table shows the amphotericin B susceptibility for a selection of medically important fungi.
Available formulations
Intravenous
Amphotericin B alone is insoluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubil ...
in normal saline
Saline (also known as saline solution) is a mixture of sodium chloride (salt) and water. It has a number of uses in medicine including cleaning wounds, removal and storage of contact lenses, and help with dry eyes. By injection into a vein it ...
at a pH of 7. Therefore, several formulations have been devised to improve its intravenous bioavailability. Lipid-based formulations of amphotericin B are no more effective than conventional formulations, although there is some evidence that lipid-based formulations may be better tolerated by patients and may have fewer adverse effects.
Deoxycholate
The original formulation uses sodium deoxycholate
Deoxycholic acid is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and chenodeoxycholic acid. Bacteria me ...
to improve solubility. Amphotericin B deoxycholate (ABD) is administered intravenously
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
. As the original formulation of amphotericin, it is often referred to as "conventional" amphotericin.
Liposomal
In order to improve the tolerability of amphotericin and reduce toxicity, several lipid formulations have been developed. Liposomal formulations have been found to have less renal toxicity than deoxycholate, and fewer infusion-related reactions. They are more expensive than amphotericin B deoxycholate.
AmBisome (LAMB) is a liposomal formulation of amphotericin B for injection
Injection or injected may refer to:
Science and technology
* Injective function, a mathematical function mapping distinct arguments to distinct values
* Injection (medicine), insertion of liquid into the body with a syringe
* Injection, in broadca ...
and consists of a mixture of phosphatidylcholine, cholesterol and distearoyl phosphatidylglycerol that in aqueous media spontaneously arrange into unilamellar vesicles that contain amphotericin B. It was developed by NeXstar Pharmaceuticals (acquired by Gilead Sciences
Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...
in 1999). It was approved by the FDA in 1997. It is marketed by Gilead in Europe and licensed to Astellas Pharma
is a Japanese multinational pharmaceutical company, formed on 1 April 2005 from the merger of and . On February 5, 2020, the company announced management changes effective from April 1, 2020.
Astellas is a member of the Mitsubishi UFJ Finan ...
(formerly Fujisawa Pharmaceuticals) for marketing in the US, and Sumitomo Pharmaceuticals in Japan.
Lipid complex formulations
A number of lipid complex preparations are also available. Abelcet was approved by the FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
in 1995. It consists of amphotericin B and two lipids in a 1:1 ratio that form large ribbon-like structures. Amphotec is a complex of amphotericin and sodium cholesteryl sulfate in a 1:1 ratio. Two molecules of each form a tetramer that aggregate into spiral arms on a disk-like complex. It was approved by the FDA in 1996.
By mouth
An oral preparation exists but is not widely available. The amphipathic nature of amphotericin along with its low solubility and permeability has posed major hurdles for oral administration given its low bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
. In the past it had been used for fungal infections of the surface of the GI tract such as thrush, but has been replaced by other antifungals such as nystatin
Nystatin, sold under the brandname Mycostatin among others, is an antifungal medication. It is used to treat '' Candida'' infections of the skin including diaper rash, thrush, esophageal candidiasis, and vaginal yeast infections. It may also be ...
and fluconazole
Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to prevent ...
.
However, recently novel nanoparticulate drug delivery systems such as AmbiOnp, nanosuspensions, lipid-based drug delivery systems including cochleates, self-emulsifying drug delivery systems, solid lipid nanoparticles and polymeric nanoparticles—such as Amphotericin B in pegylated polylactide coglycolide copolymer nanoparticles—have demonstrated potential for oral formulation of amphotericin B.
Side effects
Amphotericin B is well known for its severe and potentially lethal side effects. Very often, it causes a serious reaction soon after infusion (within 1 to 3 hours), consisting of high fever, shaking chills, hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
, anorexia
Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...
, nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
, headache
Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches.
Headaches can occur as a result ...
, dyspnea
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathing, breathe well enough. The American Thoracic Society defines it as "a subjective experience of brea ...
and tachypnea
Tachypnea, also spelt tachypnoea, is a respiratory rate greater than normal, resulting in abnormally rapid and shallow breathing.
In adult humans at rest, any respiratory rate of 1220 per minute is considered clinically normal, with tachypnea be ...
, drowsiness
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
, and generalized weakness. The violent chills and fevers have caused the drug to be nicknamed "shake and bake". The precise etiology of the reaction is unclear, although it may involve increased prostaglandin synthesis and the release of cytokines from macrophages. Deoxycholate formulations (ABD) may also stimulate the release of histamine from mast cells and basophils. Reactions sometimes subside with later applications of the drug. This nearly universal febrile response necessitates a critical (and diagnostically difficult) professional determination as to whether the onset of high fever is a novel symptom of a fast-progressing disease, or merely the effect of the drug. To decrease the likelihood and severity of the symptoms, initial doses should be low, and increased slowly. Paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
, pethidine
Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid analgesic, pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemis ...
, diphenhydramine
Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected into a vein ...
, and hydrocortisone
Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, ...
have all been used to treat or prevent the syndrome, but the prophylactic use of these drugs is often limited by the patient's condition.
Intravenously administered amphotericin B in therapeutic doses has also been associated with multiple organ damage. Kidney damage
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can b ...
is a frequently reported side effect, and can be severe and/or irreversible. Less kidney toxicity has been reported with liposomal formulations (such as AmBisome) and it has become preferred in patients with preexisting renal injury. The integrity of the liposome is disrupted when it binds to the fungal cell wall, but is not affected by the mammalian cell membrane, so the association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains its less nephrotoxic effects.
In addition, electrolyte imbalances such as hypokalemia
Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...
and hypomagnesemia
Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, an ...
are also common. In the liver, increased liver enzymes and hepatotoxicity
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...
(up to and including fulminant liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...
) are common. In the circulatory system, several forms of anemia and other blood dyscrasias (leukopenia
Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...
, thrombopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
), serious cardiac arrhythmias
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
(including ventricular fibrillation
Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the ventricles of the heart quiver. It is due to disorganized electrical activity. Ventricular fibrillation results in cardiac arrest with loss of consciousness and no p ...
), and even frank cardiac failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, an ...
have been reported. Skin reactions, including serious forms, are also possible.
Interactions
Drug-drug interactions may occur when Amphorectin B is coadministered with the following agents:
* Flucytosine
Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication. It is specifically used, together with amphotericin B, for serious ''Candida'' infections and cryptococcosis. It may be used by itself or with other antifungals for ...
: Toxicity of flucytosine is increased and allows a lower dose of amphotericin B. Amphotericin B may also facilitate entry of flucystosine into the fungal cell by interfering with the permeability of the fungal cell membrane.
* Diuretics or cisplatin
Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, br ...
: Increased renal toxicity and increased risk of hypokalemia
* 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 ...
s: Increased risk of hypokalemia
* Imidazole Antifungals
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-ad ...
: Amphorectin B may antagonize the activity of ketoconazole
Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...
and miconazole
Miconazole, sold under the brand name Monistat among others, is an antifungal medication used to treat ring worm, pityriasis versicolor, and yeast infections of the skin or vagina. It is used for ring worm of the body, groin (jock itch), and fee ...
. The clinical significance of this interaction is unknown.
* Neuromuscular-blocking agents: Amphorectin B-induced hypokalemia may potentiate the effects of certain paralytic agents.
* Foscarnet
Foscarnet (phosphonomethanoic acid), known by its brand name Foscavir, is an antiviral medication which is primarily used to treat viral infections involving the Herpesviridae family. It is classified as a pyrophosphate analog DNA polymerase inhib ...
, ganciclovir
Ganciclovir, sold under the brand name Cytovene among others, is an antiviral medication used to treat cytomegalovirus (CMV) infections.
Ganciclovir was patented in 1980 and approved for medical use in 1988.
Medical use
Ganciclovir is indicated f ...
, tenofovir
Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for preven ...
, adefovir
Adefovir is a prescription medicine used to treat (chronic) infections with hepatitis B virus. A prodrug form of adefovir was previously called bis-POM PMEA, with trade names Preveon and Hepsera. It is an orally administered nucleotide analog reve ...
: Risk of hematological and renal side effects of amphotericin B are increased
* Zidovudine
Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child ...
: Increased risk of renal and hematological toxicity .
* Other nephrotoxic drugs (such as aminoglycosides): Increased risk of serious renal damage
* Cytostatic drugs: Increased risk of kidney damage, hypotension, and bronchospasms
* Transfusion of leukocytes: Risk of pulmonal (lung) damage occurs, space the intervals between the application of amphotericin B and the transfusion, and monitor pulmonary function
Mechanism of action
Amphotericin B binds with ergosterol
Ergosterol (ergosta-5,7,22-trien-3β-ol) is a sterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells. Because many fungi and protozoa cannot survive without ergosterol, the ...
, a component of fungal cell membranes, forming pores that cause rapid leakage of monovalent ion
In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with other atoms when it forms chemical compounds or molecules.
Description
The combining capacity, or affinity of a ...
s ( K+, Na+, H+ and Cl−) and subsequent fungal cell death. This is amphotericin B's primary effect as an antifungal agent. It has been found that the amphotericin B/ergosterol bimolecular complex that maintains these pores is stabilized by Van der Waals interactions. Researchers have found evidence that amphotericin B also causes oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
within the fungal cell, but it remains unclear to what extent this oxidative damage contributes to the drug's effectiveness. The addition of free radical
A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing.
Ageing
Ailments of unknown cause
Biogerontology
Biological processes
Causes of death
Cellular processes
Gerontology
Life extension
Metabo ...
scavengers or antioxidant
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
s can lead to amphotericin resistance in some species, such as ''Scedosporium prolificans
''Lomentospora prolificans'' is an emerging opportunistic fungal pathogen that causes a wide variety of infections in immunologically normal and immunosuppressed people and animals. It is resistant to most antifungal drugs and infections are often ...
'', without affecting the cell wall.
Two amphotericins, amphotericin A and amphotericin B, are known, but only B is used clinically, because it is significantly more active ''in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
''. Amphotericin A is almost identical to amphotericin B (having a C=C double bond between the 27th and 28th carbons), but has little antifungal activity.
Mechanism of toxicity
Mammalian and fungal membranes both contain sterols, a primary membrane target for amphotericin B. Because mammalian and fungal membranes are similar in structure and composition, this is one mechanism by which amphotericin B causes cellular toxicity. Amphotericin B molecules can form pores in the host membrane as well as the fungal membrane. This impairment in membrane barrier function can have lethal effects. Ergosterol, the fungal sterol, is more sensitive to amphotericin B than cholesterol, the common mammalian sterol. Reactivity with the membrane is also sterol concentration dependent. Bacteria are not affected as their cell membranes do not usually contain sterols.
Amphotericin administration is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines.
Biosynthesis
The natural route to synthesis includes polyketide synthase
Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
components.
The carbon chains of Amphotericin B are assembled from sixteen 'C2' acetate and three 'C3'propionate units by polyketide syntheses (PKSs). Polyketide biosynthesis begins with the decarboxylative condensation of a dicarboxylic acid extender unit with a starter acyl unit to form a β-ketoacyl intermediate. The growing chain is constructed by a series of Claisen reactions. Within each module, the extender units are loaded onto the current ACP domain by acetyl transferase (AT). The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain. Ketoreductase (KR), dehydratase (DH) and enoyl reductase (ER) enzymes may also be present to form alcohol, double bonds or single bonds. After cyclisation, the macrolactone core undergoes further modification by hydroxylation, methylation and glycosylation. The order of these processes is unknown.
History
It was originally extracted from ''Streptomyces
''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...
nodosus'', a filamentous
The word filament, which is descended from Latin ''filum'' meaning " thread", is used in English for a variety of thread-like structures, including:
Astronomy
* Galaxy filament, the largest known cosmic structures in the universe
* Solar filament ...
bacterium
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
, in 1955, at the Squibb Institute for Medical Research from cultures of an undescribed streptomycete isolated from the soil collected in the Orinoco River
The Orinoco () is one of the longest rivers in South America at . Its drainage basin, sometimes known as the Orinoquia, covers , with 76.3 percent of it in Venezuela and the remainder in Colombia. It is the fourth largest river in the wor ...
region of Venezuela
Venezuela (; ), officially the Bolivarian Republic of Venezuela ( es, link=no, República Bolivariana de Venezuela), is a country on the northern coast of South America, consisting of a continental landmass and many islands and islets in th ...
. Two antifungal substances were isolated from the soil culture, Amphotericin A and Amphotericin B, but B had better antifungal activity. For decades it remained the only effective therapy for invasive fungal disease until the development of the azole
Azoles are a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom (i.e. nitrogen, sulfur, or oxygen) as part of the ring.
Their names originate from the Hantzsch–Widman nomenclature. Th ...
antifungals in the early 1980s.
Its complete stereo structure was determined in 1970 by an X-ray structure of the N-iodoacetyl derivative. The first synthesis of the compound's naturally occurring enantiomeric form was achieved in 1987 by K. C. Nicolaou
Kyriacos Costa Nicolaou ( el, Κυριάκος Κ. Νικολάου; born July 5, 1946) is a Cypriot-American chemist known for his research in the area of natural products total synthesis. He is currently Harry C. and Olga K. Wiess Professor of ...
.
Formulations
It is a subgroup of the macrolide antibiotics, and exhibits similar structural elements. Currently, the drug is available in many forms. Either "conventionally" complexed with sodium deoxycholate (ABD), as a cholesteryl sulfate complex (ABCD), as a lipid complex (ABLC), and as a liposomal
A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug deliver ...
formulation (LAMB). The latter formulations have been developed to improve tolerability and decrease toxicity, but may show considerably different pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
characteristics compared to conventional amphotericin B.
Names
Amphotericin's name originates from the chemical's amphoteric
In chemistry, an amphoteric compound () is a molecule or ion that can react both as an acid and as a base. What exactly this can mean depends on which definitions of acids and bases are being used.
One type of amphoteric species are amphiproti ...
properties.
It is commercially known as Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec, and Halizon.
References
External links
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AmBisome Summaries of Product Characteristics (United Kingdom)
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Aldols
Antifungals for dermatologic use
Antifungals
Antiprotozoal agents
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Nephrotoxins
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Polyketide antibiotics
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