Pilocarpine isolation

Botanical name Commercial name or source Alkaloids present Percentage total alkaloid (on dry wt.) Percentage pilocarpine isolated as nitrate Refer- ences... 

The extraction of alkaloids from jaborandi has been dealt with by Wurtzen, and the estimation of pilocarpine in the drug and its preparations by Jowett and by Bourcet and more recently by Taran and by Shupe.ii Elvidge has devised a colorimetric method based on Ekkert s test, < and a polarographic study has been made by Kirkpatrick. Tlie two first-pamed authors depend on the isolation of pilocarpine nitrate, which is also the basis of the process of manufacture described by Cheninitius.12... 

Pilosine, CjgHjgOgNj, obtained by Pyman (and almost simultaneously by L ger and Roques, who named it carpidine) from mother liquors remaining after the isolation of pilocarpine and isopilocarpine from the total alkaloids of P. mi.crophyllus, crystallises from alcohol in large colourless plates, m.p. 187°, [a]n + 39-9° (EtOH), lasvorotatory in alkaline solution. The salts do not crystallise readily the sulphate,. H SO, forms clusters of plates, m.p. 194-5°, fajD + 21° (HgO) the acid tartrate, B. H2C4HiOg, has m.p. 135-6°, [a]n + 24-2°, and the aurichloride, B. HAuCb, m.p. 143-4°. 

The use of natural products as medicine has invoked the isolation of active compounds the first commercial pure natural product introduced for therapeutic use is generally considered to be the narcotic morphine (1), marketed by Merck in 1826, and the first semi-synthetic pure dmg aspirin (2), based on a natural product salicin (3) isolated from Salix alba, was introduced by Bayer in 1899. This success subsequently led to the isolation of early dmgs such as cocaine, codeine, digitoxin (4), quinine (5), and pilocarpine (6), of which some are still in use. ... 

The basic alkaloid in Pilocarpus jaborandi (Rutaceae) is pilocarpine, a molecule of which contains an imidazole nucleus and is also used as a clinical drug. During alkaloid synthesis, L-histidine can produce the manzamine nucleus (Figure 27). These alkaloids are quite widespread, though they were first isolated in the late 1980s in marine sponges. They have an unusual polycyclic system and a very broad range of bioactivities. Common alkaloids with this nucleus include manzamine A, manzamine B, manzamine X, manzamine Y, sextomanzamine A and so on. 

Cetylpyridinium chloride Inclusion of 0.02% cetylpyridinium chloride with pilocarpine nitrate applied topically to the rabbit eye was found to cause a miotic effect 10 times that obtained in the absence of cetylpyridinium [64]. In another study, cetylpyridinium chloride was shown to enhance penicillin penetration across the isolated rabbit cornea [65] with an intact epithelial layer. The penetration was even more than that shown by the de-epithelialized corneas. 

Loftssona et al. [98] found that with increases in the concentration of HP-(3-CD, the flux of a hydrophobic drug arachidonylethanolamide increased. Later, Tirucherai and Mitra [99] found that HP-(3-CD could also enhance the corneal permeation of the lipophilic drug ganciclovir dibutyrate (acyl ester prodrug of ganciclovir). Aktas [100] also found that addition of HP-(3-CD to the simple aqueous solution of pilocarpine nitrate increased the permeation of pilocarpine nitrate by four times in an in vitro permeability study using isolated rabbit cornea. 

Aktas et al. [141] showed an increased permeation of pilocarpine nitrate com-plexed with hydroxy-propyl-P-cyclodextrin using isolated rabbit cornea. They found a significant reduction in the pupil diameter compared to a simple aqueous solution... 

The phenomenon of isomerization of pilocarpine to isopilocarpine was already discussed in 1880. The change takes place under a wide variety of conditions, which were reviewed earlier (7). Dopke and d Heureuse (54) in 1968 proved that the isomerization (inter alia an undesirable side reaction occurring during the isolation of pilocarpine from plant material) is not caused by an opening of the lactone ring, but proceeds via epimerization at... 

Epiisopiloturine (57), in addition to pilocarpine, was isolated in 1978 by Voigtlander et al. (117) from the leaves of a variety of Pilocarpus micro-no H... 

In 1973, Khuong-Huu et al. isolated three alkaloids anantine (94), cyno-metrine (95), and cynodine (96), from the leaves of Cynometra ananta, a plant of the Leguminoseae family native to Zaire. The structures were deduced on the basis of spectral and chemical evidence (752). The structures bear some similarity to that of pilocarpine (7), which contains a lactone ring instead of a lactam ring. Treatment of cynometrine with polyphosphoric acid yielded the N-methylated anantine (97). The latter compound could not be prepared by a simple N-methylation of anantine. Hydrolysis of cynodine afforded cynometrine and benzoic acid. 

Comparative visual and potentiometric titrations of salts of pilocarpine have been reported. The structurally interesting spinaceamine (24 R = H) and 6-methylspinaceamine (24 R = Me), isolated from amphibian venoms, have been shown to possess antimicrobial activity. ... 

Further studies on the antidiarrheal effects of berberine and the crude herb Geranii Herba were undertaken, utilizing different diarrhea models of mice, as well as on the contractions of isolated guinea pig intestinal smooth muscle and rat intestinal peristalsis. The results were compared with those obtained after administration of atropine and papaverine. Berberine significantly inhibited both the castor oil- and BaCl2-induced diarrheas at oral doses higher than 25 mg/kg, but did not inhibit pilocarpine- or serotonin-induced diarrhea even at 250 mg/kg. Berberine inhibited acetylcholine- or BaCl2-induced contractions of the ileum and colon at a concentration of about 10 5 g/ml, and exhibited a noncompetitive inhibition of the contractile response induced by acetylcholine, whereas atropine displayed a competitive inhibition. Finally, berberine inhibited spontaneous intestinal peristalsis [258]. 

The total synthesis of casimiroedine (17), isolated from Casimiroa edulis, has been achieved. The synthesis also establishes the trans-cinnamamide stereochemistry, a point which had remained unresolved in the original structural elucidation study. The reaction of the keto-lactone (18) with the imidazolyl-lithium (19) generated in situ yields a number of products,the major ones being the pilocarpine-related (20) and the ditetrahydrofuran (21). Treatment... 

A closer examination by Stuckert and Sartori (39) using the Straub perfused isolated frog heart indicated that aUocryptopine, at concentrations of 1 X 10 to 0.5 X 10, produced a decrease in the amplitude of contraction and a slowed frequency of beat. If the concentration were further increased, atrioventricular (5 4) blocks appeared. That this action of aUocryptopine appeared to be one of a direct action on the myocardium as substantiated, in that the action was not altered by atropine, acetylcholine, physostigmine, or pilocarpine. The direct myocardial stimulatory... 

Pilocarpine (13) has been synthesized by a new and improved procedure (Scheme 1). Furfural (8) was air-oxidized in sunlight to give the dihydrofuran (9) in 44 % yield, which upon Michael condensation with diethyl ethylmalonate afforded the lactone (10) in almost quantitative yield. Two conventional steps then led to ( )-homopilopic acid (11). Treatment of the acid chloride of (11) with sodio di-t-butyl acetamidomalonate followed by acidic hydrolysis and decarboxylation gave the a-aminoketone (12) without isolation of intermediates. The latter compound yielded ( )-pilocarpine (13) using previously reported but not experimentally described steps. 

Four well-defined alkaloids, pilocarpine (I), its stereoisomer isopilocarpine, pilocarpidine (II) and pilosine (III), have been isolated from jaborandi and their structures have been fully elucidated. In addition,... 

A. St. Hil. of two further alkaloids, i -pilocarpine and i -jaborine both were amorphous, optically inactive bases which were not completely characterized. D. Parodi (22) described the isolation of a weak base, jaborandine, C20H12O6N2 ( ), melting point 110°, from a sample of Paraguay jaborandi derived from a Piper species, and E. Harnack and... 

The presence of alkaloids in jaborandi was first reported by M. Byasson (73) and the principal alkaloid, pilocarpine, was isolated independently by A. W. Gerrarci (74-77) and E. Hardy (78) both of whom characterized it by the preparation of several crystalline salts. A. Petit and M. Polonovski (50) showed the presence of a second alkaloid, isomeric with pilocarpine although pilocarpine is easily converted into the new base under a variety of conditions (see Section 5), they maintained that it also occurs in the leaves and is not purely an artifact formed during the isolation processes. Jowett (28) named this base isopilo-... 

Pilocarpine undergoes isomerization to isopilocarpine under a wide variety of conditions. E. Harnack and H. Meyer (23) first observed that pilocarpine undergoes a change when heated alone or with hydrochloric acid. The product was said to be identical with a base which they had already isolated from jaborandi and had named jaborine, and which was apparently isomeric with pilocarpine. Other investigators (158, 26)... 

The reverse change can also be achieved to a small extent when isopilocarpine is heated with alcoholic potash for 3 hours, a little pilocarpine can be isolated from the product (35). The nature of the isomerism of the two bases will be discussed in a later section. 

---