Ipecacuanha

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P Ward - One of the best experts on this subject based on the ideXlab platform.

  • gr205171 a novel antagonist with high affinity for the tachykinin nk1 receptor and potent broad spectrum anti emetic activity
    Regulatory Peptides, 1996
    Co-Authors: C.j. Gardner, D R Armour, D T Beattie, J D Gale, G J Kilpatrick, D J Twissell, A.b. Hawcock, P Ward
    Abstract:

    Abstract It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-emetic activity in a range of species. To optimise this activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitutions at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-emetic activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, Ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by Ipecacuanha. GR205171 has the most potent anti-emetic activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent.

  • the broad spectrum anti emetic activity of the novel non peptide tachykinin nk1 receptor antagonist gr203040
    British Journal of Pharmacology, 1995
    Co-Authors: C.j. Gardner, J D Gale, G J Kilpatrick, D J Twissell, C.c. Jordan, Tim J Dale, Chas Bountra, P Ward
    Abstract:

    1. Following our earlier observations that the tachykinin NK1 receptor antagonist CP-99,994 is an effective anti-emetic in ferrets, we have examined the anti-emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2. In ferrets, GR203040 (0.1 mg kg-1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, Ipecacuanha or morphine. 3. In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg-1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline-treated animals continued to vomit. 4. GR203040 (0.1 mg kg-1 s.c.) retains anti-emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment. 5. GR203040 (0.1 mg kg-1 i.v.) is fully effective against Ipecacuanha-induced emesis in the dog. 6. GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret. 7. In conclusion, GR203040 is a novel anti-emetic agent, and the broad spectrum of anti-emetic activity, together with activity observed in three species, suggests that this compound is worthy of clinical investigation.

  • anti emetic profile of a non peptide neurokinin nk1 receptor antagonist cp 99 994 in ferrets
    European Journal of Pharmacology, 1993
    Co-Authors: Chas Bountra, D J Twissell, C.c. Jordan, Tim J Dale, C.j. Gardner, K T Bunce, P Ward
    Abstract:

    In the ferret, 5-HT3 receptor antagonists are effective in controlling emesis produced by cytotoxic agents or radiation. To investigate the possibility that substance P has a role, as well as 5-HT, in the emetic reflex pathway, we have examined the anti-emetic effects of a NK1 receptor antagonist (racemic CP-99,994) in the ferret. Racemic CP-99,994 was effective against a range of emetogens, comprising cytotoxic drugs, radiation, morphine, Ipecacuanha and copper sulphate.

Toni M. Kutchan - One of the best experts on this subject based on the ideXlab platform.

  • three new o methyltransferases are sufficient for all o methylation reactions of ipecac alkaloid biosynthesis in root culture of psychotria Ipecacuanha
    Journal of Biological Chemistry, 2010
    Co-Authors: Taiji Nomura, Toni M. Kutchan
    Abstract:

    Abstract The medicinal plant Psychotria Ipecacuanha produces ipecac alkaloids, a series of monoterpenoid-isoquinoline alkaloids such as emetine and cephaeline, whose biosynthesis derives from condensation of dopamine and secologanin. Here, we identified three cDNAs, IpeOMT1–IpeOMT3, encoding ipecac alkaloid O-methyltransferases (OMTs) from P. Ipecacuanha. They were coordinately transcribed with the recently identified ipecac alkaloid β-glucosidase Ipeglu1. Their amino acid sequences were closely related to each other and rather to the flavonoid OMTs than to the OMTs involved in benzylisoquinoline alkaloid biosynthesis. Characterization of the recombinant IpeOMT enzymes with integration of the enzymatic properties of the IpeGlu1 revealed that emetine biosynthesis branches off from N-deacetylisoipecoside through its 6-O-methylation by IpeOMT1, with a minor contribution by IpeOMT2, followed by deglucosylation by IpeGlu1. The 7-hydroxy group of the isoquinoline skeleton of the aglycon is methylated by IpeOMT3 prior to the formation of protoemetine that is condensed with a second dopamine molecule, followed by sequential O-methylations by IpeOMT2 and IpeOMT1 to form cephaeline and emetine, respectively. In addition to this central pathway of ipecac alkaloid biosynthesis, formation of all methyl derivatives of ipecac alkaloids in P. Ipecacuanha could be explained by the enzymatic activities of IpeOMT1–IpeOMT3, indicating that they are sufficient for all O-methylation reactions of ipecac alkaloid biosynthesis.

  • The New β-D-Glucosidase in Terpenoid-Isoquinoline Alkaloid Biosynthesis in Psychotria Ipecacuanha
    The Journal of biological chemistry, 2008
    Co-Authors: Taiji Nomura, Alfonso Lara Quesada, Toni M. Kutchan
    Abstract:

    Ipecac alkaloids produced in the medicinal plant Psychotria Ipecacuanha such as emetine and cephaeline possess a monoterpenoid-tetrahydroisoquinoline skeleton, which is formed by condensation of dopamine and secologanin. Deglucosylation of one of the condensed products N-deacetylisoipecoside (1 alpha(S)-epimer) is considered to be a part of the reactions for emetine biosynthesis, whereas its 1 beta(R)-epimer N-deacetylipecoside is converted to ipecoside in P. Ipecacuanha. Here, we isolated a cDNA clone Ipeglu1 encoding Ipecac alkaloid beta-D-glucosidase from P. Ipecacuanha. The deduced protein showed 54 and 48% identities to raucaffricine beta-glucosidase and strictosidine beta-glucosidase, respectively. Recombinant IpeGlu1 enzyme preferentially hydrolyzed glucosidic Ipecac alkaloids except for their lactams, but showed poor or no activity toward other substrates, including terpenoid-indole alkaloid glucosides. Liquid chromatography-tandem mass spectrometry analysis of deglucosylated products of N-deacetylisoipecoside revealed spontaneous transitions of the highly reactive aglycons, one of which was supposed to be the intermediate for emetine biosynthesis. IpeGlu1 activity was extremely poor toward 7-O-methyl and 6,7-O,O-dimethyl derivatives. However, 6-O-methyl derivatives were hydrolyzed as efficiently as non-methylated substrates, suggesting the possibility of 6-O-methylation prior to deglucosylation by IpeGlu1. In contrast to the strictosidine beta-glucosidase that stereospecifically hydrolyzes 3 alpha(S)-epimer in terpenoid-indole alkaloid biosynthesis, IpeGlu1 lacked stereospecificity for its substrates where 1 beta(R)-epimers were preferred to 1 alpha(S)-epimers, although ipecoside (1 beta(R)) is a major alkaloidal glucoside in P. Ipecacuanha, suggesting the compartmentalization of IpeGlu1 from ipecoside. These facts have significant implications for distinct physiological roles of 1 alpha(S)- and 1 beta(R)-epimers and for the involvement of IpeGlu1 in the metabolic fate of both of them.

Takao Tanahashi - One of the best experts on this subject based on the ideXlab platform.

C.j. Gardner - One of the best experts on this subject based on the ideXlab platform.

  • gr205171 a novel antagonist with high affinity for the tachykinin nk1 receptor and potent broad spectrum anti emetic activity
    Regulatory Peptides, 1996
    Co-Authors: C.j. Gardner, D R Armour, D T Beattie, J D Gale, G J Kilpatrick, D J Twissell, A.b. Hawcock, P Ward
    Abstract:

    Abstract It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-emetic activity in a range of species. To optimise this activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitutions at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-emetic activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, Ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by Ipecacuanha. GR205171 has the most potent anti-emetic activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent.

  • the broad spectrum anti emetic activity of the novel non peptide tachykinin nk1 receptor antagonist gr203040
    British Journal of Pharmacology, 1995
    Co-Authors: C.j. Gardner, J D Gale, G J Kilpatrick, D J Twissell, C.c. Jordan, Tim J Dale, Chas Bountra, P Ward
    Abstract:

    1. Following our earlier observations that the tachykinin NK1 receptor antagonist CP-99,994 is an effective anti-emetic in ferrets, we have examined the anti-emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2. In ferrets, GR203040 (0.1 mg kg-1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, Ipecacuanha or morphine. 3. In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg-1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline-treated animals continued to vomit. 4. GR203040 (0.1 mg kg-1 s.c.) retains anti-emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment. 5. GR203040 (0.1 mg kg-1 i.v.) is fully effective against Ipecacuanha-induced emesis in the dog. 6. GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret. 7. In conclusion, GR203040 is a novel anti-emetic agent, and the broad spectrum of anti-emetic activity, together with activity observed in three species, suggests that this compound is worthy of clinical investigation.

  • anti emetic profile of a non peptide neurokinin nk1 receptor antagonist cp 99 994 in ferrets
    European Journal of Pharmacology, 1993
    Co-Authors: Chas Bountra, D J Twissell, C.c. Jordan, Tim J Dale, C.j. Gardner, K T Bunce, P Ward
    Abstract:

    In the ferret, 5-HT3 receptor antagonists are effective in controlling emesis produced by cytotoxic agents or radiation. To investigate the possibility that substance P has a role, as well as 5-HT, in the emetic reflex pathway, we have examined the anti-emetic effects of a NK1 receptor antagonist (racemic CP-99,994) in the ferret. Racemic CP-99,994 was effective against a range of emetogens, comprising cytotoxic drugs, radiation, morphine, Ipecacuanha and copper sulphate.

Kayo Yoshimatsu - One of the best experts on this subject based on the ideXlab platform.

  • Tissue culture of medicinal plants: Micropropagation, transformation and production of useful secondary metabolites
    Bioactive Natural Products (Part N), 2008
    Co-Authors: Kayo Yoshimatsu
    Abstract:

    Abstract Plant tissue culture studies were carried out for the preservation of medicinal plant resources and efficient production of pharmaceutically important secondary metabolites. Micropropagation methods for Cephaelis Ipecacuanha were established and these methods enabled much more efficient propagation of plants than the conventional methods using seedling or layering. The C. Ipecacuanha plants propagated through tissue culture grew uniformly in the field and they constituted relatively high alkaloid contents compared to the plants grown from seedling. Adventitious root cultures of Cephaelis Ipecacuanha and Duboisia myoporoides-D. leichhardtii hybrid were grown. These root cultures produced sufficient amount of pharmaceutically important alkaloids (emetine and cephaeline in C. Ipecacuanha ; scopolamine and hyoscyamine in Duboisia hybrid ) in MS liquid medium supplemented with IAA chloro-derivatives. The alkaloid yields from cultured roots of C. Ipecacuanha , grown for seven weeks in 50 ml MS liquid medium containing 0.01 mg/l 5,6-Cl 2 -IAA are comparable to those from roots of a one-year-old plant cultivated in a greenhouse. Transformed cultures of Duboisia myoporoides-D. leichhardtii hybrid, Atropa belladonna , Cephaelis Ipecacuanha , Digitalis lanata and Papaver somniferum have been established by infection with Agrobacterium rhizogenes , and the production of important pharmaceuticals of plant origin by these cultures was successfully demonstrated. In the case of Digitalis lanata hairy roots, it was elucidated that the greening of the roots under the light stimulated cardenolides formation. Transgenic plants were successfully obtained from the transformed cultures of Atropa belladonna , Cephaelis Ipecacuanha and Papaver somniferum , in line with the molecular breeding of these plants using Agrobacterium rhizogenes . Furthermore, the production of low morphine Papaver somniferum plants, which mainly contain codeine, was first achieved by transformation of Agrobacterium rhizogenes .

  • transformation of ipecac cephaelis Ipecacuanha with agrobacterium rhizogenes
    Planta Medica, 2003
    Co-Authors: Kayo Yoshimatsu, Koichiro Shimomura, Mami Yamazaki, Kazuki Saito, Fumiyuki Kiuchi
    Abstract:

    : Transformed root cultures of ipecac (Cephaelis Ipecacuanha A. Richard), one of the recalcitrant woody plant species for Agrobacterium-mediated transformation, were established by co-culturing of in vitro petiole segments with Agrobacterium rhizogenes ATCC 15 834. Southern blot analysis of the established roots revealed that only the TL-DNA was integrated into the plant genome without incorporation of the TR-DNA. The transformed roots grew slowly on phytohormone-free solid medium and adventitious shoots were regenerated after over 6 months of culture on HF, half-strength Murashige and Skoog (1/2 MS) medium in the dark. The individually separated transformed shoots developed into plantlets on phytohormone-free solid medium at 25 degrees C under 16 h/day light, and the plants demonstrated wider leaves, shorter internodes and vigorous root growth compared to non-transformed plants. Effects of basal media and auxins on the growth and the ipecac alkaloid production of the transformed roots were investigated either under light or in the dark. The roots cultured in the dark grew well in Gamborg B5 (B5) liquid medium containing 0.5 mg/L IBA and yielded 112 mg/L of cephaeline and 14 mg/L emetine after 8 weeks of culture.

  • Plant regeneration on cultured root segments of Cephaelis Ipecacuanha A. Richard
    Plant Cell Reports, 1994
    Co-Authors: Kayo Yoshimatsu, Koichiro Shimomura
    Abstract:

    Simple one step micropropagation system for Cephaelis Ipecacuanha A. Richard was developed using root cultures grown in vitro . Adventitious shoots were directly formed on the cut end of root segments without callus formation, on phytohormone-free B5 solid medium in the dark. When the shoots attached with root segments were further cultured under 16 h light / 8 h dark, they developed into plantlets, which could be transplanted to soil. The regenerated plants grew well in a greenhouse with showing normal appearance and accumulated alkaloids. The influence of auxin on adventitious shoot formation was also investigated.

  • Improved analysis of emetic alkaloids in tissue cultures and regenerates of Cephaelis Ipecacuanha by ion pair high performance liquid chromatography
    Phytochemical Analysis, 1993
    Co-Authors: Kayo Yoshimatsu, Koichiro Shimomura
    Abstract:

    An ion pair high performance liquid chromatographic (HPLC) system for emetic alkaloids was improved using sodium 1-heptanesulphonate as a counter ion. This HPLC system enabled the simultaneous determination of emetine, cephaeline and protoetnetine in the leaf extract of a regenerated plant of Cephaelis Ipecacuanha.

  • Emetic alkaloid formation in root culture of Cephaelis Ipecacuanha
    Phytochemistry, 1991
    Co-Authors: Kayo Yoshimatsu, Koichiro Shimomura
    Abstract:

    Abstract Adventitious root cultures of Cephaelis Ipecacuanha were established from leaf segments of shoot culture in vitro . The contents of emetic alkaloids in the roots and cultured medium were quantified by HPLC. The effects of auxins and basal medium for the production of emetic alkaloids in root culture were investigated. Roots cultured in MS liquid medium supplemented with 0.01 mg 1 − 5,6-Cl 2 -IAA for seven weeks yielded 0.6 mg emetine and 2.4 mg cephaeline.