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Harpagophytum procumbens (aka Devil’s Claw, Grapple Apple) is a desert plant which is indigenous to Southern and Eastern Africa. It is found in abundance in the Kalahari Desert and Namibian steppes[i], where it has long been used as a folk remedy to treat a variety of illnesses, including fevers, skin lesions, gout, rheumatoid arthritis and conditions affecting the gall bladder, pancreas, stomach and kidneys1 [ii]. It was introduced into Europe via Germany in the beginning of the 20^th century, where attention has focused on its use as an anti-inflammatory and anti-rheumatic herb.

Main Active Constituents

The therapeutic parts of the plant are the secondary tuberised roots.1 Researchers have discovered that these contain a complex mixture of chemical constituents, including:

Iridoid Glycosides (0.5 – 3%)[iii]

Harpagoside was the first glycoside to be isolated from Harpagophytum procumbens in 1962 and is widely regarded as the main active constituent of Harpagophytum1 [iv]. Another glycoside discovered at the same time was named harpagide.1 A third glycoside procumbine was isolated in 1964[v]. In 1983, three additional iridoid glycosides with similar names, but having different linkages were discovered.1 2

Figure 1 Main Iridoid Glycosides from Harpagophytum procumbens3

Iridoids are synthesised through the mevalonic acid pathway and are technically known as cyclopentan-[c]-pyran monoterpenoids.[vi] The aglycones of the iridoid glycosides have a furane or pyrane structure. By degradation of natural pentoses to furfuol this gives rise via furane-2-carbonic acid to furane. The pyranes a-pyrane and gamma pyrane in their reactions resemble unsaturated aliphatic compounds, but the pyrylium salts derived from them are trebly unsaturated and so are aromatic in character.2 Some researchers believe that the therapeutic effects of the glycosides are due to furane and pyrane, the latter accepting hydrogen and thus producing oxidation of the substrate, such as a toxin.1 2

Studies conducted have revealed that the iridoid glycosides from Harpagophytum procumbens are hydrolysed into the pyridine monoterpene alkaloid Aucubinine B by human fecal bacteria.[vii]

Flavonoids

Luteolin, kaempferol1 3 5

Phenolic Acids

Chlorogenic acid, cinnamic acid, caffeic acid1 3 5

Quinones

Harpagoquinone1 3

Phytosterols

Stigmasterol, b-Sitosterol1 3 5

Sugars (50%)3

Consisting mainly of the tetrasaccharide stachyose (up to 46%)3 , smaller amounts of raffinose, sucrose and monosaccharides.1 2 3 With the absence of starch and high molecular weight polysaccharides, the sugars serve as reserve carbohydrate and lead to an unusually high water-soluble fraction of 50-70%.3

Triterpenes1 3

Oleanolic3 8 , Ursolic3 , and 3b-acetyloleanolic acid derivatives1 3

Other

Acetoside[viii]

Esters1

Minerals: Ca, Cr, Fe, Mg, Mn, K, P, Se, Si, Zn 8

Pharmacology

Anti-inflammatory/Analgesic/Antirheumatic Activity

Much research has been conducted on animals and humans over the past 3-4 decades to scientifically validate the effectiveness of Harpagophytum and the iridoid glycoside harpagoside as an anti-inflammatory, anti-rheumatic and analgesic agent. The results of these studies have been conflicting.

Early studies conducted by a noted European scientist Professor Zorn in 1957 on rats with formaldehyde induced arthritis showed significant reductions in swelling of arthritic joints following sub-cutaneous injection and oral ingestion of an infusion of Harpagophytum. Thus he concluded that Harpagophytum contained a potent anti-inflammatory or anti-rheumatic substance and that was equivalent to the best synthetic drug with this effect.2   Subsequent tests were undertaken by another group of scientists (Eichler & Koch) in 1970 to determine whether the isolated constituent, harpagoside yielded the same results. While the results with the isolated substance were good, they were not nearly as effective as those utilising the whole plant extract, adding that there was also very little analgesic effect from the herb.2 As a result, they concluded that the anti-rheumatic effects were not merely due to a lessening of discomfort, but actually produced a real improvement in the condition.1

During the period 1961 to 1972 excellent results were reported with Harpagophytum in the treatment of over 350 patients with a variety of disorders ranging from rheumatic disease, arthritis and athrosis to diseases of the liver, gall bladder, stomach, intestines and kidneys.1 2 One notable success story was Dr. F Schmidt, who reported favourable results treating 200 rheumatic patients with infusions of Harpagophytum root taken over long periods of time. He also experienced significant pain relief and mobility within 10 minutes of injecting Harpagophytum extract into his own arthritic knee joint.1

While several contemporary pharmacological studies on animals and clinical trials in humans have supported these earlier findings about Harpagophytum, concluding that its anti-inflammatory effects were similar to or greater than potent non-steroidal anti-inflammatory agents (NSAIDs) such as phenylbutazone[ix] [x] and indomethacin, and its analgesic effects compared favourably to acetylsalicylic acid.1   Other studies have indicated that Harpagophytum has little if any anti-inflammatory, anti-rheumatic or analgesic activity.1 10 [xi] Studies conducted by Grahame and Robinson on both rats and humans using oral administration of Harpagophytum proved ineffective in reducing inflammation and reported no significant improvement in the majority of arthritis sufferers.11 [xii] Another study conducted amount 118 patients with back pain failed to substantiate the effectiveness of orally administered Harpagophytum extract in relieving back pain.4

As a result of these conflicting results, several authors have cited a lack of quality control (standardisation) of the preparations used in the studies, and the inactivation of Harpagophytum extracts by oral administration due to the deactivation of its active constituents by gastric acid juices3 as possible causes for these discrepancies. There is some evidence to support the latter, with research indicating that the anti-inflammatory and analgesic effects of Harpagophytum were abolished following an acid treatment in order to reproduce the physio-chemical conditions found in the stomach.7 [xiii]  The same treatment also abolished the analgesic effects of harpagoside, suggesting it is also degraded by gastric acid.9

One area where researchers appear to be in agreement is that the isolated iridoid glycoside harpagoside does not appear to be involved in the anti-inflammatory properties of Harpagophytum.1 9 10 In addition, while harpagoside does appear to exhibit some analgesic activity, this effect was 42% less than the whole plant extract at double the dosage1 , indicating that other compounds in the herb must also be involved.9

The mechanism underlying the anti-inflammatory and anti-arthritic action of Harpagophytum is unclear. Research conducted in the early seventies indicated that Harpagophytum’s anti-arthritic action was due to the redox potential of the iridoid glycosides (refer iridoid glycosides above).2 More recent studies have indicated that the anti-inflammatory action does not appear to involve the arachadonic acid cascade and prostaglandins, as do conventional NSAIDs, such as indomethacin.1 9 10 12 [xiv]

It is believed that the analgesic action of Harpagophytum may be due a complex interaction between Harpagophytum’s various active principles, suggesting that these, especially harpagoside interfere with the mechanisms which regulate calcium in the cells. [xv]

Anti-oxidant Activity

Recent research has centred on the possibility that Harpagophytum possesses significant anti-oxidant action and that this action may explain some of its other actions, particularly the anti-inflammatory and anti-rheumatic actions. There has been accumulating evidence that oxidative free radicals may be responsible for the induction of inflammation and may be an important etiological factor in the genesis of inflammatory diseases, such as rheumatoid arthritis (RA). Oxidative free radicals produced by polymorphonuclear leukocytes, and possibly other sources, contribute to the complex pathogenesis of arthritic disease. Thus they activate prostaglandin synthesis, and cause direct cellular injury, altering the biochemical biophysical and structural properties of cellular proteins, including elastin, collagen and polysaccharides; degrading cartilage and reducing the viscosity of synovial fluid. It has been shown that RA has many characteristics of a free-radical induced disease.[xvi] The human synovial tissue has no anti-oxidant protection in the form of superoxide dismutase (SOD), catalase (CAT) or glutathione peroxidase (GPX), to protect against potential damage induced by oxygen free radicals. This would include lipid peroxidation and its consequences. Experimental studies were conducted in rats to investigate the anti-oxidant activity of Harpagophytum extract in terms of its effects on SOD, CAT GPX and lipid peroxidase (LP) activities in rat brain frontal cortex and striatum. Harpagophytum extract (100 and 200mg/kg) was administered intra-peritoneally for 14 days and the results were compared with those elicited from a standard anti-oxidant Deprenyl. Harpagophytum exhibited a dose-related increase in SOD, CAP and GPX activities in both brain areas concomitant with a reduction in LP activity; similar to the results produced by Deprenyl. These results indicate that Harpagophytum exhibits significant anti-oxidant activity, which may be responsible for its reported experimental and clinical anti-inflammatory activity.16

This anti-oxidant action may also explain some of the other reported actions of Harpagophytum, including its inhibitory effect on reperfusion-induced ventricular arrhythmias in animals and interference with mechanisms that regulate the influx of calcium into cells.16 Reperfusion injury following myocardial infarction is associated with an accumulation of oxidative free radicals. Anti-oxidants have shown to be effective in preventing or reducing such injury. Similarly, increased cellular influx, following lipid peroxidation of the cell membrane, may be involved in mechanisms underlying cell damage.16

Digestive Activity

Harpagophytum is reported to have a bitter action, equivalent to that of gentian root.1 5 Much of this effect is thought to be due to its iridoid glycosides which cause reflex stimulation of the digestive processes.3 In addition, research has shown that it activates liver function, promoting detoxification of toxins such as urea.2 It has also proven useful for reducing raised cholesterol and neutral fat levels in patients with metabolic disorders.1 5

Findings have been published relating to the beneficial results of Harpagophytum in the treatment of a range of digestive disturbances including dyspeptic conditions of the upper epigastrium, intestinal upsets, and liver and gall bladder complaints with or without pancreatic involvement.5

Immunomodulatory Activity

Harpagophytum has been shown to exhibit significant immunomodulatory activity16 and according to traditional Indian medicine, Harpagophytum is a good stimulant to the lymphatic system.2

Toxicology

The toxicology of Harpagophytum procumbens is considered very low.1 To date, there have been no reported side effects following its use.1 4 11 A toxicological study on rats concluded that none of the doses produced any symptoms of incompatibility or adverse reactions.1

Contraindications

Harpagophytum procumbens is said to have oxytocic properties and should be avoided in pregnancy.1 In addition, due to its reflex effect on the digestive system, it should be avoided in patients with gastric or duodenal ulcers.3

Conclusion

Scientific research conducted over the past 4 decades to validate the effectiveness of Harpagophytum as an anti-inflammatory, analgesic and anti-rheumatic agent has produced conflicting results. Nevertheless, it has been established that the iridoid glycoside harpagoside does not exhibit anti-inflammatory or anti-rheumatic activity in isolation and thus any such activity exhibited by Harpagophytum is due to the complex interaction of its individual constituents. Considering Harpagophytum’s long history of usage in Africa, as well as the positive results reported by a growing number of researchers and herbalists using the whole plant to treat rheumatism and various other disorders, not to mention its absence of side effects when compared to the pharmacological alternatives, such as NSAIDs, this herb warrants further consideration by scientists and herbal medicine practitioners in the future.