Académique Documents
Professionnel Documents
Culture Documents
ANTHRAQUINONE GLYCOSIDES
M. Ahsan Khalid, B.Pharm, Pharm. D B.Pharm,
M.Phil Scholar (RIPS/RIU) HIPSHIPS-HUKIC
Anthraquinone Structure
Anthracene glycosides are oxygenated derivatives of pharmacological importance that are used as laxatives or cathartics, anti-inflammatory, antibacterial, antifungal and also antias natural dyes. dyes.
O
tautomerization
OH
Oxidation Reduction
H Anthranol
OH
Anthrone
Oxanthrone
Reduction
O
8 9 10 5 4 1
Oxidation
O Anthraquinone
Anthracene glycosides
and less commonly in aglycone form free aglycones have to be removed in assay because inactive
Introduction to Anthraquinones
Historically: Rhubarb, Senna, Aloes and Cascara were all used as purgative drugs. Monocotyledons: Only Liliaceae.
Dicotyledons: Rubiaceae, Leguminosae, Polygonaceae, Rhamnaceae, Ericaceae, Euphorbiaceae, Lythraceae, Saxifragaceae, Scrophulariaceae and Verbenacacea. Also in certain fungi and lichen.
Reduced anthraquinone derivatives Occur either freely (aglycones) or as glycosides. Isomers Anthrone: Parent structure (pale yellow, nonnonsoluble in alkali, non-fluorescent) nonAnthronol: brown-yellow, soluble in alkali, brownstrongly fluorescent
Anthronol derivatives (e.g. in Aloe have similar properties fluorescence used for identification)
Oxanthrones
Found in Cascara bark Intermediate products (between anthraquinones and anthranols) When oxidised form anthraquinones
Accomplished via Modified Borntragers Test (oxanthrones oxidised using hydrogen peroxide)
Dianthrones
Derived from 2 anthrone molecules 2 molecules may/not be identical Form easily due to mild oxidation of anthrones Form important aglycones
flat molecule can get into gut mucosa and irritate eventually causing peristalsis
4 aglycone structures
all existing in any of the 3 forms phenolic group is the irritant principle
Aloe-emodin
Emodin
Aglycones:
OH
OH
OH
OH
OH
OH
OH
OH
HO
CH3
CH 2OH
CH3
COOH
Emodin
Aloe-emodin
Chrysophanol
Rhein
1- monoglucoside at C8
O-linked
2- diglucoside at C1 andC8
3- C- glycosides C
all types combined to give complex mixture in the plant assays different since each compound has different purgative potency
They are derived from two anthracene unites connected by covalent C-C bond through C-10. C-
HomoHomo-Dianthrones:
The two anthrone moieties are similar. e.g. Sennidins A&B and their similar. corresponding glycosides Sennosides A&B. They are all formed of A&B. two Rhein monomers. The A group are (l)-form while the B group are monomers. (l)meso compounds with zero optical rotation. rotation.
OR O OH
HOOC
COOH
OH
R= H R= Glc R= H R= Glc = = = =
OR
Sennidin A Sennoside A Sennidin B Sennoside B
Hetero-Dianthrones: Hetero-Dianthrones:
The two anthrone moieties are different. e.g. Sennidins C&D and their different. corresponding glycosides Sennosides C&D. They are all formed of one C&D. Rhein and one Aloe-emodin monomers. The C group are (l)-form while Aloemonomers. (l)the D group are meso compounds with zero optical rotation. rotation.
OR
OH
HOOC
CH2OH
OH
R= H R= Glc R= H R= Glc = = = =
OR
Sennidin C Sennoside C Sennidin D Sennoside D
Glycosides:
O-glycosides:
e.g. Cascarosides A & B. They are both O- and C-glycosides. Each one OCcontain two sugar unites. OH Glc O O
R1
R= Glc, R1= H R= H, R1= Glc
CH2OH
Cascaroside A Cascaroside B
C-glycosides:
OH O OH
e.g. Barbaloin it is formed from the removal of one sugar from Cascarosides. Cascarosides.
CH2OH H Glc
Mechanism of action
Potency:
Aglycones not therapeutically active in animals lipid soluble absorbed in stomach and never reach colon to produce a local effect
Mechanism of Action:
The glycosides are absorbed from the small intestine and re-excreted in the large reintestine where they increase the motility so produce laxation. laxation. Aglycones produce griping effect so it is recommended to prescripe antispasmodic with them.
Highly active phenolic group irritant to mucosa Glycosides very water soluble reach large intestine where they are hydrolysed by E.coli enzymes become lipid soluble absorbed into circulation on way through gut wall disturb Aubach nerve plexus causing smooth muscle to contract peristalsis 5-8 hours to act
take night before in low doses drug metabolised by liver and recirculated via bile to give more effect people esp elderly can become reliant on them needing higher dose to produce an effect carcinogenic Melanosis coli
StructureStructure-Activity Relationship:
Glycosylation is essential for activity. Hydroxylation at C-1 and C-8 is essential for activity. CCOxidation level at C-9 and C-10 is important: CC
Highest level of oxidation (anthraquinones) have the lowest activity. Oxanthrones are less active than anthrones. Complete reduction of C-9 and C-10 eliminates the activity. CC-
Substitution at C-3 have great impact on activity: CCH2OH > CH3 > COOH
Extraction
Water/alcohol or mixtures of them used Dried plant material percolation in industrial columns with dilute alcohol Tincture produced Partitioned with chloroform/ether to clean up (remove green pigment, fats, lipids) Clean yellow tincture subjected to column chromatography Gradual elution of individual glycosides Crystallised for purity
Identification:
Easy coloured orange-yellow orangeChemical test: Borntragers test in alkali (KOH, NH3) phenolic groups -> phenate complex (bright red) TLC using silica gel plates do not have to be sprayed since yellow but can confirm with KOH (red spot) Mass spectrometry
Assay
Difficult each component in mixture has different potency Safest assay is:
spectroscopy quick and cheap, more accurate but gives same emphasis to each compound
To remove aglycones
discard ether phase containing free aglycones then acid hydrolyse aqueous phase containing glycosides with ferric chloride for direct C- bonds C and with dilute HCl
extract in CHCl3
Chemical test:
Borntragers and Modified Borntragers test:
For Aglycones:
Extract plant material with organic solvent. Shake with NH4OH OR KOH. Boil plant material with dil. HCl for 10 min, filter and shake with organic solvent (Ether or Benzene). Separate the organic solvent. Shake with NH4OH OR KOH. Boil plant material with dil. HCl/FeCl3, filter and shake with organic solvent (Ether or Benzene). Separate the organic solvent. Shake with NH4OH OR KOH.
For O-Glycosides: O
For C-Glycosides: C
Positive result indicated by Rose Red colour in the aqueous alkaline layer.
Senna: Senna:
Leaves and pods contain Sennosides A-D. The C-C bond protect the anthrone from oxidation. C-
Contain Cascarosides A- D. Barbaloin present as a secondary glycoside in Cascara. Cascara. They are O- and C-glycosides. OCThe C-linked glucose at C-10 protect anthrones from CCoxidation.
Aloes:
The major glycoside in Aloes is the C-glycoside Barbaloin. CBarbaloin. Barbaloin is primary glycoside in Aloes. The C-linked glucose at C-10 protect anthrones from CCoxidation.
Rhubarb: Rhubarb:
It
is purgative only in large doses. It contains high amount of tannins that have astringent effect.
SENNA
Senna - Leguminosae
Definition: Consists of the dried leaflets of Cassia senna (Alexandrian senna), or Cassia angustifolia (Tinnevelly senna).
Indigenous to Africa (tropical regions) Used since 9th 10th century Introduced into medicine by Arab physicians (used both the leaves and pods) Exported by Alexandria name of the Sudanese drug.
Collected in September Whole branches bearing leaves are dried in the sun. Pods and large stalks are separated with sieves. Leaves are graded (whole leaves, whole leaves and half-leave halfmix, siftings). Whole leaves sold to public
Senna - Collection
Senna - Constituents
Sennoside A Sennoside B
Chemical constituents:
(i) 1 and 1,8 O glucosides
= 1st series glycosides aglycones: rhein, aglycones: rhein, aloe emodin
dimer can be split into two parts with FeCl3 hydrolysis and monomer aglycones assayed for
Senna - Constituents
Kaempferol (yellow flavanol) + glucoside (kaempferin) kaempferin) Mucilage Calcium oxalates Resin
Macroscopical
Macroscopical
Seldom larger than 4 cm in length GreyGrey-green Asymmetric at base Broken and curled at edges Few press markings
Seldom exceeds 5cm in length YellowYellow-green Less asymmetric at base Seldom broken and normally flat Often shows impressions (mid vein)
Microscopical
Microscopical
Hairs numerous (approximately 3 epidermal cells apart) Most stomata have 2 subsidiary cells
Hairs less numerous (approximately 6 epidermal cells apart) Stomata have 2-3 2subsidiary cells with the respective ratio 7:3
Chemical Tests
Chemical Tests
Ether extract of hydrolysed acid solution of herb with methanolic magnesioum acetate solution gives
Same Test
TLC
TLC
Bombay, Mecca and Arabian Sennas (found in Cassia angustifolia from Arabia). Dog senna Cassia obovata Cassia auriculata Indian Senna Cassia podocarpa
Substitutes or Adulterants
Senna Fruit
Definition: Senna pods are the dried, ripe fruits of Cassia senna and Cassia angustifolia, angustifolia, which are commercially known as Alexandrian and Tinnevelly senna pods respectively. Both have separate monographs
Pods are collected with the leaves and dried in a similar fashion. After separation of the leaves, the pods are handhand-picked into various qualities, the finer being sold (commercially), while the finer pieces are used to make galenicals.
Active constituents found in the pericarp Similar to those actives of the leaves
Sennoside A Sennidin
Senna - Uses
Laxatives (habitual constipation or occasional use). Lacks astringent after-effect (Rhubarb) after
Senna - Additional
ContraContra-indications
Medicinal Actions Vermifuge, diuretic, febrifuge Other uses: laxative candy (bitter taste).
Should not be used with cardiac glycosides. Seeds/pods give gentler action than leaves: more appropriate for the young, elderly and those prone to stomach cramps. NB: Over-use causes Overdependency. Overdose: nausea, bloody diarrhoea, vomiting and nephritis. LongLong-term use: dehydration & electrolyte depletion, worsening constipation and weakening intestinal muscles.
Topically: poultice prepared with vinegar to treat pimples. NOTE: Senna may cause urine to become reddish no clinical significance.
CASCARA
Definition: Official cascara sagrada is the dried bark of Rhamnus purshianus. purshianus. Bark is collected from wild trees (depletion is leading to the increase of cultivation)
Cascara
collected, dried and stored for 12 months ( anthraquinone content -> less toxic) discovered 100 years ago Rocky Mtns, W.Coast, US Mtns, W.Coast, griping action harder to eliminate
modern substance
Use: Use: night before to clear bowels for x-rays and barium meal
Etymology
Rhamnos Greek, branch, shiny shrub. Purshiana after Pursh, botanist 1st described herb in 1814.
Recently introduced to Modern Medicine. Known to early Mexican and Spanish priests. Not introduced to medicine until 1877.
Collected form mid-April to end of midAugust, when it separates readily from the rest of the trunk. Longitudinal incisions are made 10cm apart and the bark removed. Tree is then usually felled and the branch bark separated. Bark is then dried in the shade with the cork facing upwards. This is referred to as natural cascara. Commercial supplies are comminuted to give small, even fragments called evenized, processed, or compact cascara.
During preparation and storage the bark should be protected from rain and damp (partial extraction of constituents may occur or bark may become mouldy). Should be stored for at least 1 year before use (although no longer a BP requirement). Bark appears to increase in medicinal value up unto its 4 years old (stored bark)
When stored for at least a year better tolerated by patient (less griping pains due to increased peristalsis) Yet as effective as fresh bark. Reason?
Due to Hydrolysis and other changes that occur during storage. Bitter taste of Cascara can also be reduced by treating the bark with alkali (alkali earths or MgO).
Chemical constituents:
(i) 4 primary glycosides
O- and C- linkages C-
barbaloin derived from aloe-emodin aloechrysaloin derived from chrysophanol derived from emodin oxanthrone, aloe-emodin, chrysophanol oxanthrone, aloe-emodin, incl. emodin, aloe-emodin, chrysophanol, herterodianthrones emodin, aloe-emodin, chrysophanol, palmidin A B C
2 aloins:
C Glycosides Breakdown products of Cascarosides A-D A
Barbaloin
Dianthrones
Those from Emodin Aloe-emodin Aloe Chrysophanol
Hetrodianthrones
Palmidin
A, B and C (Rhubarb)
Rhamnus alnifolia (too rare) Rhamnus crocea (bark is very different from official drug) Rhamnus californica (so closely related to Rhamnus purshianus some botanists do not consider them to be separate species). Rhamnus fallax
Physiological Action
Excessive use: nausea, vomiting, heamatorrhoea. Long term use: Weakens intestinal muscles. ContraContra-indications: children younger than 14, during pregnancy, lactation, IBS, Crohns, intestinal obstruction, and idiopathic abdominal pain.
Medicinal Uses Move stagnation, clear heat. The most widely used laxative worldworld-wide. Topically: Used as a wash for herpes lesions
RHUBARB
Rhubarb - Polygonaceae
Definition: Rhubarb/Chinese Rhubarb is the rhizome of Rheum palmatum. Other palmatum. species and hybrids of Rheum, except R. Rheum, rhaponticum, may rhaponticum, also be included.
Chinese Rhubarb has a long history. Mentioned in a herbal of 2700BC. Formed an important article of commerce on the Chinese trade routes to Europe. Still used medicinally today.
Rhizomes are grown at high altitudes (+3000m). Collected in Autumn or spring (6-10yrs old) (6Cork is removed, cut. Artificially dried. Packed in tin-lined tinwooden cases. Inferior quality herbs are packed in hessian bags
Anthraquinones without a carboxyl group chrysophanol, emodin, aloealoe-emodin & physcion. Also the glycosides of these substances.
Free anthraquinones: anthraquinones: chrysophanol, emodin, aloe-emodin aloeand rhein. Some of the above constituents may also occur as glycosides.
Bitter stomachic Diarrhoea (low doses) contains tannins Purgative (high doses) followed by an astringent effect. Suitable only for occasional for occasional use, not for chronic constipation.
Rhubarb - Additional
Etymology
Topical Uses:
Medicinal Actions
Poultice to treat boils, burns, wounds. Used to stop bleeding (tannins stypic and astringent). Used as a mouthwash for oral ulcers.
Other uses: Acid content: fresh root can be used to polish brass. Caution
ALOE VERA
General Information
Member of the lily family. 240 species of Aloe. Aloe Vera, Aloe Barbadensis. Succulent, perennial, evergreen. Very hardy. Native to Africa, but is now widespread. It is a bitter herb with a wide range of medicinal properties. It contains over 75 compounds, many of which are biologically active.
Aloe - Liliaceae
Definition: Aloes are the solid residue obtained by evaporating the liquid which drains from the transversely cut leaves of various Aloe species. The juice is usually concentrated by boiling and solidifies on cooling.
Official varieties are the Cape Aloes from SA and Kenya (Aloe ferox), and (Aloe ferox), the Curacao Aloes from West Indies (Aloe barbadensis). barbadensis).
Dark brown or GreenGreenbrown Glassy masses Thin fragments have a deep olive colour SemiSemi-transparent.
Powder: green-yellow greenRub 2 pieces of drug together powder is found on the surfaces. Characteristic sour odour (rhubarb/apple(rhubarb/apple-tart odour). Taste: nauseous and bitter. Microscopy: powder in lactophenol amorphous.
Colour: yellow-brown yellowchocolate brown. Poor qualities (overheated) black colour. Opaque Breaks with a waxy facture SemiSemi-transparent More opaque on keeping. Nauseous and bitter taste. Characteristic iodoform odour. Microscopy: lactophenol acicular crystals
Aloes - Constituents
Aloin
Barbaloin Isobarbaloin
AloeAloe-emodin
Aloe - Constituents
Unlike C-glycosides, O-glycosides of COAloe are not hydrolysed by heating with dilute acids or alkali. Can be decomposed with ferric NB: chloride & dilute HLC - NB: Modified Borntragers Test oxidative hydrolysis. Anthraquinones give a red colour when shaken with dilute ammonia.
NB: All Aloes give a strong green fluorescence with borax (characteristic of anthranols) General test for aloes.
History
Known as the lily of the desert. Considered the plant of immortality by many native peoples. Very long history of medical usage 2200 B.C.- Mentioned on Sumerian B.C.clay tablets. 1550 B.C.- The Ebers Papyrus states B.C.12 recipes for mixing Aloe with other agents to treat human disorders. Usually the whole leaf was ground and mixed with another medicinal agent. Used by Cleopatra and Nerfertiti. Nerfertiti.
History Continued
400 B.C.- Extensively traded in the Near East B.C.and Asia. 333 B.C.- The Island of Socotra was captured by Alexander B.C.the Great because of its Aloe supplies. 68 A.D.- Dioscorides wrote a detailed description of Aloe A.D.vera and all of its uses. 200 A.D.- Aloe vera was an important part of Roman A.D.medicine and became extremely popular in Europe in the centuries to come. 1500 A.D.- Introduced to the New World by the Conquistadors A.D.-
Modern History
First modern medical paper published in 1934. Described how the whole leaf was used to treat radiation dermatitis. Many papers published in the 20th century describing a wide range of medicinal properties. Reports have mainly focused on the antidiabetic, antidiabetic, anticancer, and antimicrobial properties of the whole leaf, gel, or juice of the plant. Many species of Aloe have been studied.
Vitamins
Lignins
Vitamin D, A, C, E and B12 Lipases, proteases, kinases Ca, Na, K, Mg, Mn, Cu, Zn, Mn, Cr, and Se Mono and poly saccharides, glucosaccharides, glucomannans Most important: Aloin, and Aloin, Emodin
Enzymes Minerals
Inert except when in topical treatments 3% of Aloe Vera gel Cholesterol, Campesterol, Sisosterol, Campesterol, Sisosterol, and Lupeol AspirinAspirin-like 20 amino acids
Saponins
Fatty Acids
Sugars
Salicyclic acid
Anthraquinones
Amino Acids
Normal: digestive tract absorbs nutrients into blood bacteria helps breakdown food IBS: unabsorbed food coats the bowel preventing normal absorption Symptoms:Exhaustion, Symptoms:Exhaustion, constipation, diarrhea, and indigestion Colonic Irrigation: loosed and wash out residues
Two main types of arthritis Osteoarthritis: wear and tear of life Rheumatoid: autoimmune disease Symptoms: stiff, red, swollen joints Traditional treatment: antiantiinflammatory drugs with steroids Aloe helps repair damage Mode of Action: stimulate the Cytokines Varying results
Added because of known rejuvenating action Mode of Action: Polysaccachrides act as moisturizers Stimulates the fibroblasts to replicate faster Smoothes skin because sticks epidermal cells together which normally flake Interferes with melanin deposit production which lead to liver spots
Characterized by hyperglycaemia and alterations of glucose and lipid metabolism Lead to cell damage and elevation of reactive oxygen species Must control blood glucose and lipid levels Aloe shown to reduce blood glucose in diabetic rats
Control Diabetic Control 332.27 20.80 +300 mg/kg Aloe vera 96.85.30 +600microgram/kg Glibenclamide 118.466.56
Blood Glucose (mg/dL) Plasma Insulin 85.81 5.20 15.861.38 5.120.68 14.121.48 12.520.69
Decrease in blood glucose due to stimulation of insulin secretion Decrease in cholesterol, triglycerides, phospholipids, and free fatty acids from increased clearance and decreased transporters
Anti-Microbial/Anti-Microbial/-Bacterial
50% gel leaf solution, complete inhibition of Staphylococcus aureus Due to phenolics Efficacy of gel or leaf? S. aureus inhibited by both Other bacteria inhibited by just leaf or gel
When aloe is combined with other anti-microbials, antia wound heals faster than with the anti-microbial antialone. Possibly due to its moisturizing capability as well.
Immune Booster?
Asian practice of ingesting herbs to support the immune system May have a direct inhibitory effect on microbes Also, selectively modulates cells of the immune system
Alveolar Osteitis
Dry Socket (Wisdom teeth extraction) Acemannan Hydrogel (from clear inner gel of aloe vera) vera) Normal treatment 7.6% develop AO With Acemannan 1.1% develop AO
Normal
Burn Treatment
Shows increased healing effects on 2nd degree burns AntiAnti-inflammation and wound healing promotion Vessels return to normal size quicker than with untreated burns
AloeAloe-emodin induces apoptosis in T24 human bladder cancer cells Inhibits cell viability, induces G2/M arrest MechanismMechanism- p53, p21, caspase activation Treat Radiation Symptoms?
Neuroectodermal Cancer
Inhibits neuroectodermal tumors in mice. Few toxic effects, does not inhibit normal fibroblasts. Induces apoptosis and is specific to a tumor energyenergydependent pathway of drug incorporation
Aloe emodin Regulation of cell cycle, cell proliferation and protein kinase C (PKC) Inhibits S phase Suppresses PKC activity
Aloe vera and Aloe arborescens did not suppress tumor growth Life prolongation up to 32% in mice Dose dependent
Products
Gel and latex. GelGel- leaf pulp or mucilage obtained from the parenchymal tissue. LatexLatex- bitter, yellow substance obtained from pericyclic tubules just beneath the outer skin of the leaves. (otherwise called Aloe juice) These terms are often confused by consumers. Using a freshly cut leaf is thought to be the most effective treatment.
Summary
Dental Health and Hygiene 2. Provides Rapid Soothing 3. Aids in Healthy Digestion 4. Immune Support and Function Regulates Weight and Energy Levels 6. Collagen and Elastin Repair 7. Daily Dose of Minerals 8. Daily Dose of Vitamins 9. AntiAnti-inflammatory Properties 10. Essential Amino Acids
1.
5.
Aloe - Uses
Purgative Seldom prescribed alone activity is increased when administered with small quantities of soap or alkaline salts; Carminatives moderate griping tendency. Ingredient in Friars Balsam.
Medicinal Uses:
Etymology
AntiAnti-bacterial, anti-fungal, antichologoge, emmenogogue, antianti-inflammatory (juice), antianti-inflammatory , demulcent, vulnerary, immuneimmune-stimulating (gel).
Name derives from Arabic alu, meaning shiny or bitter in reference to the gel.
Other uses
ContraContra-indications
Pregnancy & lactation (internal uses)
KhoiKhoi-San hunters rub gel on their bodies to reduce sweating and mask their scent. Used to break nail-biting nailhabit.
These are derived from the mucilage gel parenchyma cells Should not be confused with aloes (juice of pericycle juice used for laxative effect). Cosmetic industry (usefulness often exaggerated) - Used as suntan lotions, tonics and food additives. Mucilage = polysaccharide of glucomannans and pectin
COCHINEAL
Cochineal
Definition: Cochineal is the dried female insect, Dactylopius coccus, coccus, containing eggs and larvae. Insects are indigenous to Central America, commercial supplies are derived from Peru.
Eggs are protected during the rainy season are sown on cacti on which it is intended to breed. Both male and females arise. After a time, fecundation occurs. Females attach themselves to the cacti and the males die out. Females swell to x2 their original size due to developing larvae & develop red colouring matter.
Cochineal
Cochineal
Larvae mature after 14days and escape from the now dead body of the parent. Only a small portion develop into males. For next 2 weeks, males fly and young females crawl on the plant. Life cycle = 6 weeks. 3-5 generations may be produced in 1 season.
Cochineal - Collection
Insects are brushed from plants with small brooms and killed (some left to provide for subsequent crops). First crop killed contains the most colouring matter. Insects are killed by plunging them in boiling water, stove heat or exposure to fumes by burning sulphur or charcoal. If heat is used insects change to purple black called black grain. Fume killed turn purple-grey called silver purplegrain. Small immature insects and larvae which can be separated by sieves are sold as granilla or siftings.
Cochineal Collection
Cochineal - Characteristics
Oval in shape Half cm in length Examined microscopically after removing the colouring matter (ammonia solution). Each insect contains 60 450 eggs and larvae.
Cochineal - Constituents
C-glycoside anthraquinone derivative purple, water-soluble colouring matter waterCarminic acid Fat Wax
bright
Adulteration: occurs by increasing the weight of the insects by dressing it with inorganic matter in a colour which blends in with that of the insect. Detected when insects are placed in water
Anthraquinones take about 10hours to produce an effect (take overnight) Should not be used for more than 10 days. Should not be used by children, pregnant and lactating women. Cause griping pain. Are habit-forming. habitAnthraquinones = phenolic glycosides, used as an irritating laxative