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Sanguinarine & Other Eye Tension Raising Alkaloids in Plants

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Sanguinarine is a benzphenanthridine alkaloid belonging to the iso-quinoline group. Over 114 iso-quinoline alkaloids are known and some of them like morphine, codeine and papaverine are amongst the most active and useful of drugs. Iso-quinoline alkaloids are usually found in plants belonging to two large botanical families, the poppies and fumarias, but they also occur sporadically in twelve other plant families (Manske, 1954). Sanguinarine was hitherto regard­ed as a rare and obscure alkaloid first isolated 133 years ago from Sanguinaria canadensis L., the 'blood-root' used by the North American Indians to paint them­selves scarlet. During the last one and a half centuries, the "epoch of alkaloid detection", chemists found sanguinarine in only eight other poppy-fumaria plants. Working at the National Institute for Medical Research, London, under the guid­ance of Sir Robert Robinson and Dr. James Walker, we found that sanguinarine was present and abundant in most morphological parts of nearly fifty species of poppy-fumaria weeds we examined [Table - 1]. All that was required was a few milligrams of plant material ground in acetic acid, se­parated either by paper chromato­graphy or electrophoresis and com­pared with standard alkaloids. Sanguinarine, and at times ten other related alkaloids, were se­parated from a few drops of this simple extract and showed striking and beautiful fluorescent colours under filtered ultra-violet light. Sanguinarine was more or less in­variably present in the leaves and stems, often in the roots, capsules and seeds, and was the commonest fluorescent alkaloid seen in these species. It seems to have been missed for so many years because of its unusual solubility and absence of adequate .tests. The details of our methods of extrac­tion, detection, identification and results have been published else­where. (Hakim et al., 1961a).

An example of how sanguinarine had hitherto escaped chemical detec­tion is found in the 'opium' poppy Papaver somniferum L. No plant has been more thoroughly in­vestigated in the annals of chemistry, and yet sanguinarine was missed in this plant. We found it in its roots, stems and leaves. The young plants are used as edible herbs in the middle East and like the 'fumitory' herb, deliberate­ly fed to cattle.

You will realise a little later on the purpose of this elaboration into the phyto-chemistry of sanguinarine. At this stage, I am trying to bring out the widespread source of san­guinarine in plants, firstly because a few of these are directly ingested by man, and secondly, as I shall show later, a large number of such plants grow as prolific weeds in most parts of the world (Fedde, 1909; Hutchinson, 1921), are grazed upon by cattle, who absorb their toxic alkaloids, store them in their liver and secrete them in their milk.

Those of you who have seen the cornfields of Europe and North India will recollect the myriads of scarlet poppies (Papaver rhoeas L., P. hybridum L., and P. dubium L.) growing amongst the grain. Every­one of these poppies contain san­guinarine in either its roots, stems, leaves or seeds. The poppies are collected with the harvest and con­tribute their poisons both to the grain and to the dried fodder which is fed to cattle.

On this table is a vase filled with the Indian 'fumitory' (Fumaria in­dica Pugsley), an elegant weed I collected this morning from the fields of Amritsar. It grows throughout the Indo-Gangetic plain and on the hills of South India and is very similar to the soecies that grow abundantly throughout Persia, the Middle East, Europe and America. Shakespeare (1523) de­scribed the European species ([Figure - 2]-Fumaria officinalis L.) as grow­ing wild and prolific in the fields of France. The roots and seeds of both species are rich in san­guinarine. I wish to draw your special attention to this herb as it is likely to be responsible for a con­siderable number of cases of en­demic rather than epidemic glau­coma in our country, throughout the Middle East, and in other parts of the world.

The 'fumitory' herb has been widely used as a medicine, and must have contributed an insidious source of sanguinarine during its recorded history covering over 2,000 years! This herb was known as 'Kaonos' in ancient Greek classical medicine and prescribed by Dios­corides and Pliny. Under its Arabic na-ne of 'Shahtiraj', it was used by Ibn Seranion, Ibnu'l-Baytar, Ibn 'Awwam, 'Abd ar-Razzaq, Rabi Mai­monides and others and its use continued throughout the Middle East unto the present day. As 'Shahterah, it was well-known to the physicians of Persia, Ar-Razi, 'Ali ibnu'l 'Abbas al-Ma usi, Abu 'Ali Sina and Isma'il Jurjani and its use was introduced into the Mughal. school of Yunani medicine in lnaia through works like the Makhzan­el-Adwia. The herb is well known in North India as 'Sathra' (often confu­sed with 'Pitpapda'), and is com­monly used as a Yunani and even as an Ayurvedic decoction for fevers, skin and kidney diseases, blood-purification etc. Our hostess, on watching me collect the herb this morning, strongly recommended it for treatment of "women's dis­eases" (? !). So deep-rooted is this ancient tradition that not only Shakespeare but practically every ancient and modern herbal through­out Europe, extolls the virtues of the European 'fumitory' and of several species of poppies. Even the Na­tional Formulary (1960), the Dis­pensatory of the United States of America (1960) and the British Pharmaceutical Codex (1949) spon­sor the use of Sanguinaria canadensis L., the 'blood-root' over­flowing with the scarlet alkaloid sanguinarine !

Several orange-red stems and roots were prescribed as direct applications for the eyes in ancient empirical systems of medicine. These are usually from poppy-fumaria or closely related genera. The oldest extant of Ayurvedic texts - the Bower Manuscript - re­commends the application of 'rasot', an extract of berberis. Dioscorides used 'argemone', probably a thalictrum. The famous 'mamiran', from coptis, corydalis or thalictrum, was prescribed by Al-Ghafiqi in Spain, and is extensively used, even at present, in Afghanistan and North India.

The first link connecting san­guinarine to its possible aetiology in world glaucoma, was the chemi­cal investigation I have described earlier. It became evident that sanguinarine was not a rare and obscure alkaloid, but a glaucoma­genetic toxin definitely found and abundant in most parts of at least sixty-two poppy-fumaria species [Table - 1]. Since the alkaloid was present in so many species distributed in 14 representative genera, it seems very likely that it will be found in most or all of the nearly seven hundred species of this vast plant family. If you visualise rice fields in spring, teem­ing with thousands of yellow argemone, or vegetable gardens scattered with the purple fumaria in early winter, or fields of wheat amongst which thousands of scarlet poppies fill an autumn landscape, you will realise how densely just three out of these hundreds of species can grow and, therefore, what an abundant source of san­guinarine is available in the plant kingdom.

The next significant discovery was that the eye tension-raising action of sanguinarine on experimental animals is not the unique property of this alkaloid, but that several similar alkaloids also produce acute rise of eye tension in experimental animals. My early Oxford experi­ments had shown that, besides sanguinarine, chelerythrine and a ­number of crude poppy extracts when injected subconjunctivally or intra-ocularly in rabbits and mon­keys, raised their eye tension. Lieb and Scherf from Prof. Thiel's group at Frankfurt, later showed that seven out of fourteen iso-quinoline alkaloids, injected intravenously into anaesthetized rabbits, produced acute rise of eye tension. When these alkaloids were later available to me through the kindness of Dr. Manske, I produced acute rise of eve tension by their sub-con­junctival injection.

Whilst working at the National Institute for Medical Research, I found a new and very interesting technique of raising eye tension by injecting minute doses of sanguin­arine into the brain of conscious cats. The very first injection of sanguinarine given by this method in 1957, raised eye tension it was also significant that several other iso-quinoline alkaloids, besides sanguinarine, when injected into the brain also produced acute rise of eye tension [Table - 2]. As these other alkaloids, sent by Dr. Manske, belong to twelve plant families, besides poppy-fumarias, it is inter­esting to speculate if iso-quinoline alkaloids found in species of spinach, for example, or others found in the custard-apple or the Indian bael-fruit, or even in oranges and limes, may have some subtle insidious action in the aetiology of widespread glaucoma.

Sanguinarine also Transmitted Through Milk

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The detection techniques deve­loped later in London showed that the milk of goats fed on argemone leaves contained sanguinarine and other alkaloids. This transmission experiment was repeated in London on a group of lactating rabbits that were injected with sanguinarine and subsequently milked. Sanguinarine was detected from several, even 1 ml, samples of such milk. The rabbit milk also showed a green fluoresc­ing metabolite of sanguinarine which was found to be identical with synthetically prepared benz­(c)acridine, the metabolic conversion taking place in the liver (Hakim et al., 1961 b). As benz(c)acridine has the basic molecular structure of a series of the most virulent of ex­perimental carcinogenic hydrocar­bons, according to Prof. Lacassagne from the Radium Institute at Paris, I applied both sanguinarine and benz(c)acridine on the skin of a group of mice, using his method. I also implanted paraffin pellets containing these substances into the bladder of rats, and found after several months that both substances produced, papillomas and carcino­mas in mice and rats. The goat and rabbit experiments clearly proved that lactating animals if fed on sanguinarine-containing plants, could transmit glaucoma-inducing sanguinarine and cancer-inducing benz(c)acridine in their milk.

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