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50-410: Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis . The fungal infections it is used to treat include mucormycosis , aspergillosis , blastomycosis , candidiasis , coccidioidomycosis , and cryptococcosis . For certain infections it is given with flucytosine . It is typically given intravenously (injection into a vein). Common side effects include

100-531: A Teflon ring and after vacuuming, buffer is placed on the dried lipids and it is sandwiched using a second conductive cover glass. Next an electrical field with certain frequency and voltage is applied which promotes formation of GUVs. For polyunsaturated lipids, this technique can induce a significant oxidation effect on the vesicles. Nevertheless, it is a very common and reliable technique to generate GUVs. Modified approaches exist that employ gel-assisted swelling (agarose-assisted swelling or PVA-assisted swelling) for

150-511: A component of fungal cell membranes, forming pores that cause rapid leakage of monovalent ions ( 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 within

200-417: A confirmation of the fungal infection should be made. Approximately half of suspected cases of fungal infection in nails have a non-fungal cause. The side effects of oral treatment are significant and people without an infection should not take these drugs. Azoles are the group of antifungals which act on the cell membrane of fungi. They inhibit the enzyme 14-alpha-sterol demethylase, a microsomal CYP, which

250-405: 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 , pethidine , diphenhydramine , and hydrocortisone have all been used to treat or prevent

300-573: 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,

350-1018: A disk-like complex. It was approved by the FDA in 1996. 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 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 and fluconazole . 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. The oral lipid nanocrystal amphotericin by Matinas Biopharma

400-427: A doctor's prescription , but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally. Indicated when the fungal infection is located in the eye. There is currently only one ocular antifungal available. This is Natamycin. However, various other antifungal agents could be compounded in this formulation. Used occasionally when there's an infection of

450-415: A five-membered ring containing two or three nitrogen atoms. The imidazole antifungals contain a 1,3-diazole ( imidazole ) ring (two nitrogen atoms), whereas the triazole antifungals have a ring with three nitrogen atoms. Allylamines inhibit squalene epoxidase , another enzyme required for ergosterol synthesis. Examples include butenafine , naftifine , and terbinafine . Echinocandins inhibit

500-414: A fungal infection on the skin. An example is tinea pedis; this is sometimes treated with topical terbinafine. If the antifungal has good bioavailability , this is a common route to handle a fungal infection. An example is the use of ketoconazole to treat coccidioidomycosis. Like the oral route, this will reach the bloodstream and distribute throughout the body. However, it is faster and a good option if

550-891: A high-yield production of vesicles with consistent sizes. Phospholipid liposomes are used as targeted drug delivery systems. Hydrophilic drugs can be carried as solution inside the SUVs or MLVs and hydrophobic drugs can be incorporated into lipid bilayer of these liposomes. If injected into circulation of human/animal body, MLVs are preferentially taken up phagocytic cells , and thus drugs can be targeted to these cells. For general or overall delivery, SUVs may be used. For topical applications on skin, specialized lipids like phospholipids and sphingolipids may be used to make drug-free liposomes as moisturizers, and with drugs such as for anti-ultraviolet radiation applications. In biomedical research, unilamellar liposomes are extremely useful to study biological systems and mimicking cell functions. As

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600-495: A homogeneous layer of liposomes. This step removes the bulk of chloroform. To remove the residues of trapped chloroform, lipids are placed under vacuum from several hours to overnight. Next step is re-hydration where the dried lipids are re-suspended in the desired buffer. Lipids can be vortexed for several minutes to insure that all the lipid residues get re-suspended. SUVs can be obtained in via two methods. Either by sonication (for instance with 1 second pulses in 3 Hz cycles at

650-601: A kink in acyl chains which further changes the lipid packing and results in a looser packing. Therefore, the composition and sizes of the unilamellar liposomes must be chosen carefully based on the subject of the study. Each lipid bilayer structure is comparable to lamellar phase lipid organization in biological membranes , in general. In contrast, multilamellar liposomes (MLVs), consist of many concentric amphiphilic lipid bilayers analogous to onion layers, and MLVs may be of variable sizes up to several micrometers. There are several methods to prepare unilamellar liposomes and

700-410: 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. Amphotericin B is used for life-threatening protozoan infections such as visceral leishmaniasis and primary amoebic meningoencephalitis . The following table shows

750-440: A membrane bilayer , often the composition of the phospholipids is different between the inner and outer leaflets. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and sphingomyelin are some of the most common lipids most animal cell membranes. These lipids are widely different in charge, length, and saturation state. The presence of unsaturated bonds (double bonds) in lipids for example, creates

800-435: A potential human pathogen that sometimes exhibits multi-class antifungal drug resistance is concerning and has been associated with several outbreaks globally. The WHO has released a priority fungal pathogen list, including pathogens with antifungal resistance. Unilamellar liposome The composition and characteristics of the cell membrane varies in different cells (plant cells, mammalian cells, bacterial cells, etc). In

850-400: A power of 150 W) or by extrusion. In extrusion method, the lipid mixture is passed through a membrane for 10 or more times. Depending on the size of the membrane, either SUVs or LUVs can be obtained. Keeping vesicles under argon and away from oxygen and light can extend their lifetime. Natural swelling: in this method soluble lipids in chloroform are pipetted on a Teflon ring. The chloroform

900-470: A reaction with fever , chills, and headaches soon after the medication is given, as well as kidney problems . Allergic symptoms including anaphylaxis may occur. Other serious side effects include low blood potassium and myocarditis (inflammation of the heart). It appears to be relatively safe in pregnancy . There is a lipid formulation that has a lower risk of side effects. It is in the polyene class of medications and works in part by interfering with

950-428: Is a One Health concern, driven by multiple extrinsic factors, including extensive fungicidal use, overuse of clinical antifungals, environmental change and host factors. Like resistance to antibacterials, antifungal resistance can be driven by antifungal use in agriculture. Currently there is no regulation on the use of similar antifungal classes in agriculture and the clinic. The emergence of Candida auris as

1000-555: Is a liposomal formulation of amphotericin B for injection 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 in 1999). It was approved by the FDA in 1997. It is marketed by Gilead in Europe and licensed to Astellas Pharma (formerly Fujisawa Pharmaceuticals) for marketing in

1050-443: Is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic . The polyene antimycotics bind with sterols in the fungal cell membrane , principally ergosterol . This changes the transition temperature (Tg) of the cell membrane, thereby placing the membrane in a less fluid, more crystalline state. (In ordinary circumstances membrane sterols increase

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1100-551: Is a subset of antimicrobial resistance , that specifically applies to fungi that have become resistant to antifungals. Resistance to antifungals can arise naturally, for example by genetic mutation or through aneuploidy . Extended use of antifungals leads to the development of antifungal resistance through various mechanisms. Some fungi (e.g. Candida krusei and fluconazole ) exhibit intrinsic resistance to certain antifungal drugs or classes, whereas some species develop antifungal resistance to external pressures. Antifungal resistance

1150-483: Is administered intravenously . As the original formulation of amphotericin, it is often referred to as "conventional" amphotericin. 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 (liposomal amphotericin B; LAMB)

1200-519: Is allowed to evaporate and the ring is then placed under the vacuum for several hours. Next the aqueous buffer is added gently over the Teflon ring and lipids are allowed to naturally swell to form GUVs overnight. the disadvantage of this method is that a large amount of multilamellar vesicles and lipid debris are formed. Electroformation: In this method lipids are placed on a conductive cover glass (indium tin oxide or ITO coated glass) or on Pt wires instead of

1250-518: Is furthest along having completed a successful phase 2 clinical trial in cryptococcal meningitis. Amphotericin B is well known for its severe and potentially lethal side effects, earning it the nickname "amphoterrible". Very often, it causes a serious reaction soon after infusion (within 1 to 3 hours), consisting of high fever, shaking chills, hypotension , anorexia , nausea , vomiting , headache , dyspnea and tachypnea , drowsiness , and generalized weakness. The violent chills and fevers have caused

1300-413: Is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines. The natural route to synthesis includes polyketide synthase 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

1350-402: Is required for the biosynthesis of ergosterol for the cytoplasmic membrane. This leads to the accumulation of 14-alpha-methylsterols resulting in impairment of function of certain membrane-bound enzymes and disruption of close packing of acyl chains of phospholipids, thus inhibiting growth of the fungi. Some azoles directly increase permeability of the fungal cell membrane. Antifungal resistance

1400-490: Is significantly more active in vivo . 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. 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

1450-572: The cell membrane 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 in that region of Venezuela and came into medical use in 1958. It is on the World Health Organization's List of Essential Medicines . It is available as a generic medication . One of

1500-548: The US, and Sumitomo Pharmaceuticals in Japan. A number of lipid complex preparations are also available. Abelcet was approved by the FDA 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

1550-612: The amphotericin B susceptibility for a selection of medically important fungi. MIC breakpoint (mg/L) Amphotericin B alone is insoluble in normal saline 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. The original formulation uses sodium deoxycholate to improve solubility. Amphotericin B deoxycholate (ABD)

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1600-408: The central nervous system and other systemic options cannot reach the concentration required in that region for therapeutic benefit. Example(s): amphotericin B. This may be used to treat some fungal infections of the vaginal region. An example of a condition they are sometimes used for is candida vulvovaginitis which is treated with intravaginal Clotrimazole This is sometimes indicated when there's

1650-598: The chemical's amphoteric properties. It is commercially known as Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec, and Halizon. Pentavalent antimonials ( Meglumine antimoniate , Sodium stibogluconate ) 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 cryptococcal meningitis , and others. Such drugs are usually obtained by

1700-431: The circulatory system, several forms of anemia and other blood dyscrasias ( leukopenia , thrombopenia ), serious cardiac arrhythmias (including ventricular fibrillation ), and even frank cardiac failure have been reported. Skin reactions, including serious forms, are also possible. Drug-drug interactions may occur when amphotericin B is coadministered with the following agents: Amphotericin B binds with ergosterol ,

1750-439: The creation of glucan in the fungal cell wall by inhibiting 1,3-Beta-glucan synthase : Echinocandins are administered intravenously, particularly for the treatment of resistant Candida species. Incidents of liver injury or failure among modern antifungal medicines are very low to non-existent. However, some can cause allergic reactions in people. There are also many drug interactions . Patients must read in detail

1800-409: The drug has poor bioavailability. An example of this is IV amphotericin B for the treatment of coccidioidomycosis. The available classes of antifungal drugs are still limited but as of 2021 novel classes of antifungals are being developed and are undergoing various stages of clinical trials to assess performance. A polyene is a molecule with multiple conjugated double bonds . A polyene antifungal

1850-420: 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

1900-700: The enclosed data sheet(s) of any medicine. For example, the azole antifungals such as ketoconazole or itraconazole can be both substrates and inhibitors of the P-glycoprotein , which (among other functions) excretes toxins and drugs into the intestines. Azole antifungals are also both substrates and inhibitors of the cytochrome P450 family CYP3A4 , causing increased concentration when administering, for example, calcium channel blockers , immunosuppressants , chemotherapeutic drugs , benzodiazepines , tricyclic antidepressants , macrolides and SSRIs . Before oral antifungal therapies are used to treat nail disease ,

1950-467: The formation of GUVs under more biologically relevant conditions. A variety of methods exist to encapsulate biological reactants within GUVs by using water-oil interfaces as a scaffold to assemble lipid layers. This allows the use GUVs as cell-like membrane containers for the in vitro recreation (and investigation) of biological functions. These encapsulation methods include microfluidic methods, which allow for

2000-410: The fungal cell, but it remains unclear to what extent this oxidative damage contributes to the drug's effectiveness. The addition of free radical scavengers or antioxidants can lead to amphotericin resistance in some species, such as Scedosporium prolificans , without affecting the cell wall. Two amphotericins, amphotericin A and amphotericin B, are known, but only B is used clinically, because it

2050-416: 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 B administration

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2100-472: 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 and hypomagnesemia are also common. In the liver, increased liver enzymes and hepatotoxicity (up to and including fulminant liver failure ) are common. In

2150-595: The macrolactone core undergoes further modification by hydroxylation, methylation and glycosylation. The order of these three post-cyclization processes is unknown. It was originally extracted from Streptomyces nodosus , a filamentous bacterium , in 1955, at the Squibb Institute for Medical Research from cultures of an undescribed streptomycete isolated from the soil collected in the Orinoco River region of Venezuela . Two antifungal substances were isolated from

2200-461: The main uses of amphotericin B is treating a wide range of systemic fungal infections . Due to its extensive side effects, it is often reserved for severe infections in critically ill, or immunocompromised patients. It is considered first line therapy for invasive mucormycosis infections, cryptococcal meningitis , and certain aspergillus and candidal infections. It has been a highly effective drug for over fifty years in large part because it has

2250-453: The packing of the phospholipid bilayer making the plasma membrane more dense.) As a result, the cell's contents including monovalent ions (K , Na , H , and Cl ) and small organic molecules leak, which is regarded as one of the primary ways a cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. However, at therapeutic doses, some amphotericin B may bind to animal membrane cholesterol, increasing

2300-464: The protocols differ based on the type of desired unilamellar vesicles. Different lipids can be bought either dissolved in chloroform or as lyophilized lipids. In the case of lyophilized lipids, they can be solubilized in chloroform. Lipids are then mixed with a desired molar ratio. Then chloroform is evaporated using a gentle stream of nitrogen (to avoid oxygen contact and oxidation of lipids) at room temperature. A rotary evaporator can be used to form

2350-443: The risk of human toxicity. Amphotericin B is nephrotoxic when given intravenously . As a polyene's hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals. Azole antifungals inhibit the conversion of lanosterol to ergosterol by inhibiting lanosterol 14α-demethylase . These compounds have

2400-478: 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 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

2450-483: 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 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

2500-595: Was achieved in 1987 by K. C. Nicolaou . 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 formulation (LAMB). The latter formulations have been developed to improve tolerability and decrease toxicity, but may show considerably different pharmacokinetic characteristics compared to conventional amphotericin B. Amphotericin's name originates from

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