Khellin

Last updated
Khellin
Khellin.png
Khellin 3D.png
Names
Preferred IUPAC name
4,9-Dimethoxy-7-methyl-5H-furo[3,2-g][1]benzopyran-5-one
Other names
Amicardine; Corafurone; Methafrone; Kelourin; Rykellin; Visammin ; Ammispasmin; Ammivisnagen; Gynokhellan; Interkellin; Interkhellin; Amikellin; Ammipuran; Benecardin; Deltoside; Kelicorin; Khelangin; Khellamine; Khellanals; Khellinorm; Medekellin; Visammimix; Viscardan; Visnagalin; Kalangin; Kelincor
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.001.267 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 201-392-8
KEGG
MeSH C438920
PubChem CID
UNII
  • InChI=1S/C14H12O5/c1-7-6-9(15)10-11(16-2)8-4-5-18-12(8)14(17-3)13(10)19-7/h4-6H,1-3H3 X mark.svgN
    Key: HSMPDPBYAYSOBC-UHFFFAOYSA-N X mark.svgN
  • InChI=1/C14H12O5/c1-7-6-9(15)10-11(16-2)8-4-5-18-12(8)14(17-3)13(10)19-7/h4-6H,1-3H3
    Key: HSMPDPBYAYSOBC-UHFFFAOYAZ
  • O(C)c1c2C=COc2c(OC)c3OC(C)=CC(=O)c13
Properties
C14H12O5
Molar mass 260.245 g·mol−1
Appearancecolorless needle-shaped crystals
Melting point 154-155 C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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. [1] It is a major constituent of the plant Ammi visnaga , also known as Bishop's Weed. Once purified, khellin exists as colorless, odorless, bitter-tasting needle-shaped crystals [2] and is classified as a gamma-pyrone, a furanochromone derivative. In the early 20th century, researchers searched for khellin analogs with lower toxicity and better efficacy. A number of drugs were discovered through this research, such as amiodarone and cromolyn sodium, which are used in current medical practice. Efloxate is also mentioned as analog. [3]

Contents

Background

Khellin is found in Egypt, the Middle East, and areas surrounding the Mediterranean. It is a major constituent of the plant Ammi Visnaga, existing between 0.3 and 1.2% in the leaves and seeds. [4] Bishop's Weed is a name given to several species of plants; however, only Ammi Visnaga contains khellin. Khellin is rarely found in its pure form; instead it is found in Ammi Visnaga or "Khella" extract. As a result, many healing properties have been attributed to Khellin that are actually due to other constituents in the extract. Ammi Visnaga preparations are commercially available and very common; however, the amount of Khellin and other ingredients varies greatly between brands and even batches of the same brand. The extract is commonly found as a tea or in a pill form.

Medical use

Therapeutic use is often not recommended, as the risks often outweigh the benefits. Regardless of this recommendation, Ammi Visnaga is still often used in the Middle East, Egypt, and surrounding areas. Unwanted side effects include dizziness, reversible cholestatic jaundice, pseudoallergic reaction, and elevated levels of liver enzymes (transaminases and gamma-glutamyltransferase). [5]

Vitiligo

Vitiligo is a disease which causes loss of pigmentation in portions of skin. When khellin is applied topically in combination with UVA light, it is able to stimulate melanocytes (cells that produce melanin) in hair follicles for successful treatment of vitiligo. One such method is blister roof transplantation; in which, blisters are formed on an unaffected area and are then grafted onto a vitiligo affected area. When khellin is applied topically and treated with UV light, pigmentation returns to treated areas. [6] When taken systemically, khellin induces elevated liver enzyme levels and broad photosensitivity; however, topical application reduces these side effects. Psoralens are commonly used for vitiligo treatment, but have higher phototoxic and DNA mutagenic effects. While Khellin treatment in conjunction with UV therapy is successful, accelerated photoaging and increased risk of skin cancer is another concern. [7]

Kidney stones

When ammi visnaga extract is taken daily, as a tea or as a pill, calcium oxalate kidney stone formation is inhibited, making it a good treatment for hyperoxaluria (a condition in which there is excessive oxalate excretion in the urine, causing kidney stones). Khellin was thought to slow or prevent calcium oxalate nucleation, preventing stones from forming. However, studies have shown that khellin is not the active ingredient in Ammi Visnaga extract. Upon studying calcium oxalate nucleation, ammi visnaga extract as a whole was shown to prolong nucleation time as well as change stone conformation, while khellin alone had no effect. [8] [9]

Khellin has also been used to treat renal colic, which is due mostly to schistosomiasis infections and stone formation. The plant mixture had diuretic properties that were seen to relieve renal colic by relaxing the ureter and acting as a diuretic.

Other

Intramuscular injections of khellin can also be used to treat asthma. Khellin acts as a bronchodilator; however, the common side effects including nausea present difficulties. [10]

Khellin has been used to relieve the pain associated with angina pectoris by acting as a selective coronary vasodilator. [11] This can be done either orally or intramuscularly; however nausea is a major side effect regardless of how the medication is taken. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Kidney stone disease</span> Formation of mineral stones in the urinary tract

Kidney stone disease, also known as renal calculus disease, nephrolithiasis or urolithiasis, is a crystallopathy where a solid piece of material develops in the urinary tract. Renal calculi typically form in the kidney and leave the body in the urine stream. A small calculus may pass without causing symptoms. If a stone grows to more than 5 millimeters, it can cause blockage of the ureter, resulting in sharp and severe pain in the lower back or abdomen. A calculus may also result in blood in the urine, vomiting, or painful urination. About half of people who have had a renal calculus are likely to have another within ten years.

<span class="mw-page-title-main">Angina</span> Chest discomfort due to not enough blood flow to heart muscle

Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.

<span class="mw-page-title-main">Calcium oxalate</span> Calcium salt of oxalic acid

Calcium oxalate (in archaic terminology, oxalate of lime) is a calcium salt of oxalic acid with the chemical formula CaC2O4 or Ca(COO)2. It forms hydrates CaC2O4·nH2O, where n varies from 1 to 3. Anhydrous and all hydrated forms are colorless or white. The monohydrate CaC2O4·H2O occurs naturally as the mineral whewellite, forming envelope-shaped crystals, known in plants as raphides. The two rarer hydrates are dihydrate CaC2O4·2H2O, which occurs naturally as the mineral weddellite, and trihydrate CaC2O4·3H2O, which occurs naturally as the mineral caoxite, are also recognized. Some foods have high quantities of calcium oxalates and can produce sores and numbing on ingestion and may even be fatal. Cultural groups with diets that depend highly on fruits and vegetables high in calcium oxalate, such as those in Micronesia, reduce the level of it by boiling and cooking them. They are a constituent in 76% of human kidney stones. Calcium oxalate is also found in beerstone, a scale that forms on containers used in breweries.

<span class="mw-page-title-main">Oxalate</span> Any derivative of oxalic acid; chemical compound containing oxalate moiety

Oxalate (IUPAC: ethanedioate) is an anion with the formula C2O42−. This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (Na2C2O4), and several esters such as dimethyl oxalate (C2O4(CH3)2). It is a conjugate base of oxalic acid. At neutral pH in aqueous solution, oxalic acid converts completely to oxalate.

<span class="mw-page-title-main">Nifedipine</span> Calcium channel blocker medication

Nifedipine, sold under the brand names Adalat and Procardia among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. It is one of the treatments of choice for Prinzmetal angina. It may be used to treat severe high blood pressure in pregnancy. Its use in preterm labor may allow more time for steroids to improve the baby's lung function and provide time for transfer of the mother to a well qualified medical facility before delivery. It is a calcium channel blocker of the dihydropyridine type. Nifedipine is taken by mouth and comes in fast- and slow-release formulations.

<span class="mw-page-title-main">Thiazide</span> Class of chemical compounds

Thiazide refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most countries, thiazides are the least expensive antihypertensive drugs available.

<span class="mw-page-title-main">Cromoglicic acid</span> Chemical compound

Cromoglicic acid (INN)—also referred to as cromolyn (USAN), cromoglycate, or cromoglicate—is traditionally described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium. This drug prevents the release of inflammatory chemicals such as histamine from mast cells.

<span class="mw-page-title-main">Renal colic</span> Medical condition

Renal colic, also known as ureteric colic, is a type of abdominal pain commonly caused by obstruction of ureter from dislodged kidney stones. The most frequent site of obstruction is the vesico-ureteric junction (VUJ), the narrowest point of the upper urinary tract. Acute obstruction and the resultant urinary stasis can distend the ureter (hydroureter) and cause a reflexive peristaltic smooth muscle spasm, which leads to a very intense visceral pain transmitted via the ureteric plexus.

<span class="mw-page-title-main">Calculus (medicine)</span> Medical condition

A calculus, often called a stone, is a concretion of material, usually mineral salts, that forms in an organ or duct of the body. Formation of calculi is known as lithiasis. Stones can cause a number of medical conditions.

<span class="mw-page-title-main">Bladder stone (animal)</span> Common occurrence in animals

Bladder stones or uroliths are a common occurrence in animals, especially in domestic animals such as dogs and cats. Occurrence in other species, including tortoises, has been reported as well. The stones form in the urinary bladder in varying size and numbers secondary to infection, dietary influences, and genetics. Stones can form in any part of the urinary tract in dogs and cats, but unlike in humans, stones of the kidney are less common and do not often cause significant disease, although they can contribute to pyelonephritis and chronic kidney disease. Types of stones include struvite, calcium oxalate, urate, cystine, calcium phosphate, and silicate. Struvite and calcium oxalate stones are by far the most common. Bladder stones are not the same as bladder crystals but if the crystals coalesce unchecked in the bladder they can become stones.

<span class="mw-page-title-main">Ranolazine</span> Drug used to treat angina

Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient. Benefits appear smaller in women than men. It is taken by mouth.

<i>Ammi majus</i> Species of plant

Ammi majus, commonly called bishop's flower, false bishop's weed, laceflower, bullwort, etc., is a member of the carrot family Apiaceae. The plant, which has white lace-like flower clusters, has a large distribution through Southern Europe, North Africa and West and Central Asia, though it is hypothesized to be native to the Nile River Valley.

<span class="mw-page-title-main">Nephrocalcinosis</span> Medical condition caused by the deposition of calcium salts in the kidneys

Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe the deposition of poorly soluble calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate. It may cause acute kidney injury. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification in radiology. It is caused by multiple different conditions and is determined by progressive kidney dysfunction. These outlines eventually come together to form a dense mass. During its early stages, nephrocalcinosis is visible on x-ray, and appears as a fine granular mottling over the renal outlines. It is most commonly seen as an incidental finding with medullary sponge kidney on an abdominal x-ray. It may be severe enough to cause renal tubular acidosis or even end stage kidney disease, due to disruption of the kidney tissue by the deposited calcium salts.

<span class="mw-page-title-main">Medullary sponge kidney</span> Congenital disorder of urinary system

Medullary sponge kidney is a congenital disorder of the kidneys characterized by cystic dilatation of the collecting tubules in one or both kidneys. Individuals with medullary sponge kidney are at increased risk for kidney stones and urinary tract infection (UTI). Patients with MSK typically pass twice as many stones per year as do other stone formers without MSK. While having a low morbidity rate, as many as 10% of patients with MSK have an increased risk of morbidity associated with frequent stones and UTIs. While many patients report increased chronic kidney pain, the source of the pain, when a UTI or blockage is not present, is unclear at this time. Renal colic is present in 55% of patients. Women with MSK experience more stones, UTIs, and complications than men. MSK was previously believed not to be hereditary but there is more evidence coming forth that may indicate otherwise.

Primary hyperoxaluria is a rare condition, resulting in increased excretion of oxalate, with oxalate stones being common.

<i>Visnaga daucoides</i> Species of plant

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 can be found throughout the world as an introduced species.

Sodium cellulose phosphate is a drug used to treat hypercalcemia and hypercalciuria. It has been used to prevent kidney stones.

<span class="mw-page-title-main">Renal stone formation in space</span>

Renal stone formation and passage during space flight can potentially pose a severe risk to crew member health and safety and could affect mission outcome. Although renal stones are routinely and successfully treated on Earth, the occurrence of these during space flight can prove to be problematic.

<span class="mw-page-title-main">Visnagin</span> Chemical compound

Visnagin is an organic chemical compound with the molecular formula C13H10O4 It is a furanochromone, a compound derivative of chromone (1,4-benzopyrone) and furan.

<span class="mw-page-title-main">Idiopathic hypercalcinuria</span>

Idiopathic hypercalcinuria (IH) is a condition including an excessive urinary calcium level with a normal blood calcium level resulting from no underlying cause. IH has become the most common cause of hypercalciuria and is the most serious metabolic risk factor for developing nephrolithiasis. IH can predispose individuals to osteopenia or osteoporosis, and affects the entire body. IH arises due to faulty calcium homeostasis, a closely monitored process, where slight deviations in calcium transport in the intestines, blood, and bone can lead to excessive calcium excretion, bone mineral density loss, or kidney stone formation. 50%-60% of nephrolithiasis patients suffer from IH and have 5%-15% lower bone density than those who do not.

References

  1. Azim Khan, Muhammad (2014). "Phytochemistry and Medicinal Properties of Ammi Visnaga". Pak. J. Bot. 46 (3): 861–867.
  2. Shinde, P B; Laddha, K S (March 2014). "Development of new isolation technique and validated HPLC method development for khellin". Indian Journal of Natural Products and Resources. 5 (1): 40–43.
  3. Dewar, H. A.; Horler, A. R.; Newell, D. J. (1959). "A Clinical Trial of Penta-Erythritol Tetranitrate, A Khellin Derivative (Recordil), and Iproniazid in Angina of Effort". Heart. 21 (3): 315–322. doi:10.1136/hrt.21.3.315. ISSN   1355-6037. PMC   1017586 . PMID   13816307.
  4. Mesbah, M.K. (1992). "Determination of Khellin and Visnagin in Ammi visnaga fruits and in renal teas by HPLC". Egypt. J. Pharm. Sci. 33 (5–6): 897–904.
  5. Blumenthal, M; Busse, W.R.; Goldberg, A.; Gruenwald, J.; Hall, T.; Riggins, C.W.; Rister, R.S (1998). The complete German commission monographs, therapeutic guide to herbal medicines.
  6. Leeuw, J de; Assen, YJ; Bjerring, P; Neumann, HA Martino (2011). "Treatment of vitiligo with khellin liposomes, UV light and blister roof transplantation". J Eur Acad Dermatol Venereol. 25 (1): 74–81. doi:10.1111/j.1468-3083.2010.03701.x. PMID   20477914. S2CID   20632501.
  7. Plettenberg, Heidi; Assmann, Till; Ruzicka, Thomas (2003). "Childhood vitiligo and tacrolimus". Arch. Dermatol. 139 (5): 651–654. doi:10.1001/archderm.139.5.651. PMID   12756103.
  8. Vanachayangkul, P.; Chow, N.; Khan, S. R.; Butterweck, Veronika (2011). "Prevention of renal crystal deposition by an extract of Ammi visnaga L. and its constituents khellin and visnagin in hyperoxaluric rats". Urol. Res. 39 (3): 189–195. doi:10.1007/s00240-010-0333-y. PMC   3663934 . PMID   21069311.
  9. Abdel-Aal, E.A.; Daosukho, S.; El-Shall, H. (2009). "Effect of supersaturation ratio and Khella extract on nucleation and morphology of kidney stones". Journal of Crystal Growth. 311 (9): 2673–2681. Bibcode:2009JCrGr.311.2673A. doi:10.1016/j.jcrysgro.2009.02.027.
  10. Kennedy, M.C.S; Stock, J.P.P (1952). "The bronchodilator action of khellin". Thorax. 7 (1): 43–65. doi:10.1136/thx.7.1.43. PMC   1019140 . PMID   14913500.
  11. Osher, Harold; Katz, Kermit; Wagner, Donald (1951). "Khellin in the treatment of angina pectoris". The New England Journal of Medicine. 244 (9): 315–321. doi:10.1056/nejm195103012440901. PMID   14806755.
  12. Conn, James J. (1952). "The treatment of angina pectoris with khellin". Annals of Internal Medicine. 36 (5): 1173–1178. doi:10.7326/0003-4819-36-5-1173. PMID   14924454.