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PubMed1993

Pharmacokinetics and metabolism of vinca alkaloids.

The anti-mitotic vinca alkaloids, vinblastine, vincristine, vindesine and navelbine, are widely used both as single agents and in combination with other antitumour drugs in cancer chemotherapy. Data on clinical pharmacokinetics following intravenous bolus injection, continuous infusion and oral administration show that vinca alkaloids are characterized by a large apparent total distribution volume, rapid total plasma clearance and a long terminal half-life. Faecal excretion is the main elimination route of vinca alkaloids in humans. Urinary excretion of these agents is generally low. Moreover, vinca alkaloid pharmacokinetics are time- and dose-dependent and show large inter- and intraindividual variability. When studied in various in vitro hepatic models (freshly isolated human and animal hepatocytes in suspension and in primary culture, isolated liver perfusion and human hepatic microsomal fractions), the vinca alkaloids were extensively biotransformed into a number of metabolites which have not yet been identified structurally. Incubation of vindesine and vinblastine with a library of human liver microsomal fractions demonstrated the involvement of the human hepatic cytochromes P4503A in the biotransformation of these and probably other vinca alkaloids. This finding is of great importance with regard to possible drug interactions between vinca alkaloids and other drugs administered concurrently in combination cancer chemotherapy.

Biotransformation↗
PubMed1995

Alkaloids from frog skins: selective probes for ion channels and nicotinic receptors.

Amphibian skin has provided a wide range of biologically active alkaloids, many of which have unique profiles of pharmacological activity and therapeutic potential. Over three hundred alkaloids have been identified and structures of over a dozen different classes of alkaloids have been elucidated. These include the batrachotoxins, which were shown to be potent and selective activators and ligands for sodium channels, the histrionicotoxins, which were shown to be potent non-competitive blockers and ligands for nicotine receptor channel complexes, the pumiliotoxins and related allo- and homo-pumiliotoxins, which were shown to have myotonic and cardiotonic activity due to effects on sodium channels, and epibatidine, which was shown to have potent antinociceptive activity due to selective agonist activity at nicotinic receptors. These alkaloids are known in nature only in amphibian skin, except for homobatrachotoxin, which was recently identified in feathers and skin of a bird. Further classes of alkaloids from amphibian skin include monocyclic pyrrolidines and piperidines, bicyclic decahydroquinolines, pyrrolizidines, indolizidines, and quinolizidines and tricyclic gephyrotoxins, pyrrolizidine oximes, pseudophrynamines, and coccinellines. These alkaloids also have activity in ion channels. It appears likely that all of the frog skin alkaloids are taken up and sequestered into the skin from the diet, which for such amphibians consists mainly of small arthropods. The pyrrolidines, piperidines, 3,5-disubstituted pyrrolizidines and 3,5-disubstituted indolizidines appear likely to be derived from ants, the coccinellines and related tricyclics from beetles and the pyrrolizidine oximes from millipedes. The origins of the batrachotoxins, histrionicotoxins, pumiliotoxins and epibatidine are of particular interest in view of their remarkable biological activities.

Alkaloids↗
PubMedDate not supplied

[Recent results on the pharmacodynamics of Strychnos malgaches alkaloids].

Investigation of Strychnos (Loganiaceae) shrubs and trees was initiated by their traditional uses of their inherent poisons on arrows: this led to the discovery of strychnine and curare alkaloids. Subsequently, phytochemical investigation of several Strychnos species has shown great structural diversity of the alkaloid constituent which also display various biological effects, i.e. convulsive and relaxant effects on muscles, and antimicrobial, antitumor and antihypertensive properties. Ethnobotanical field work conducted in different regions of Madagascar revealed that infusion of three Strychnos species, S. mostueoides, S. myrtoides and S. diplotricha, is used in association with subcurative doses of chloroquine to treat chronic malaria. Bioassayfractionation led to the isolation of two major bioactive components, strychnobrasiline and malagashanine. Whereas strychnobrasiline is a previously known chemical compound, malagashanine is the first in a series of a new subtype of Strychnos alkaloids. These two alkaloids are devoid of intrinsic antimalarial effects, both in vitro (IC50 = 73.0 micrograms/ml for strychnobrasiline and 69.1 micrograms/ml for malagashanine) and in vivo (10 mg/kg conferred a 5% suppression of parasitemia). When these alkaloids are combined with chloroquine at doses much lower than required for antiplasmodial effects, they greatly enhance the chloroquine action in a dose dependent manner as seen by the isobologram method. Several minor alkaloids structurally related to malagashanine were also isolated from Madagascan Strychnos. They all enhance, to greater or lesser degrees, the chloroquine effectiveness. Interestingly, there is a positive correlation between the ethnomedical use of the three Strychnos species as chloroquine adjuvants and the chloroquine-potentiating effects of malagashanine and strychnobrasiline isolated from them. After preliminary toxicological studies, infusion of stem barks of S. myrtoides in association with chloroquine was successfully evaluated in a clinical setting. Additional chemical, pharmacological and toxicological work is being conducted on these alkaloids with the aim of developing purified and standardized extracts for clinical trials. These trials will be carried out in the chloroquine-resistant regions of Madagascar which are in need of inexpensive and efficient drugs for the treatment of chloroquine-resistant malaria.

Alkaloids↗
PubMed1987

Effect of polyamine biosynthetic inhibitors on alkaloids and organogenesis in tobacco callus cultures.

We studied the effects of inhibitors of ornithine decarboxylase (ODC), arginine decarboxylase (ADC) and spermidine synthase (Spd synthase) on organogenesis and the titers of polyamines (PA) and alkaloids in tobacco calli. DL-alpha-diffluromethylarginine (DFMA) and D-arginine (D-Arg), both inhibitors of ADC activity, were more effective than DL-alpha-difluromethylorinithine (DFMO), an inhibitor of ODC, in reducing titers of PA and the putrescine (Put)-derived alkaloids (nornicotine and nicotine). Dicyclohexylammonium sulfate (DCHA), an inhibitor of Spd synthase, was also more efficient than DFMO in reducing PA and alkaloid levels. Root organogenesis is inversely related to the titers of Put and alkaloids. Thus, DFMA and D-Arg, which strongly inhibit Put and alkaloid biosynthesis, markedly promote root organogenesis, while control callus with high Put and alkaloid content showed poor root organization. These results suggest that morphological differentiation is not required for activation of secondary metabolic pathways and support the view that ADC has a major role in the generation of Put going to the pyrrolidine ring of tobacco alkaloids.

Arginine↗
PubMed2002

The effect of topical natural ergot alkaloids on the intraocular pressure and aqueous humor dynamics in rabbits with alpha-chymotrypsin-induced ocular hypertension.

BACKGROUND: We previously reported that topical natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine dose-dependently reduce intraocular pressure in ocular normotensive rabbits, most likely by decreasing aqueous humor inflow. In the present study, the effects of these compounds on intraocular pressure and aqueous humor dynamics in a rabbit model for ocular hypertension were assessed. METHODS: Experiments were conducted in albino rabbits made ocular hypertensive by intracameral injection of alpha-chymotrypsin. Intraocular pressure responses to drug vehicle and seven different doses of topical natural ergot alkaloids were examined in order to obtain dose-response relationships for comparing the intraocular pressure-lowering effect and potency of these drugs. Tonographies were also performed to ascertain the actions of natural ergot alkaloids on aqueous humor dynamics in alpha-chymotrypsin-induced ocular hypertensive rabbits. RESULTS: Topical application of the natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine lowered intraocular pressure in alpha-chymotrypsin-induced ocular hypertensive rabbits in a dose-related fashion, with ergocristine displaying the greatest intraocular pressure-lowering effect. Tonographic studies revealed a decrease in the tonographic outflow facility following topical application of natural ergot alkaloids, although only the effects of both ergocristine and alpha-ergocryptine reached statistical significance. All natural ergot alkaloids tested significantly reduced the calculated aqueous humor inflow. CONCLUSION: This study suggests that the natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine effectively decrease intraocular pressure in the alpha-chymotrypsin-induced model of ocular hypertension. Since these compounds reduce the tonographic aqueous humor outflow facility, their final ocular antihypertensive effect appears to result from a remarkable reduction of the aqueous humor inflow.

Administration, Topical↗
PubMed2005

Automated multiple development thin-layer chromatography for separation of opiate alkaloids and derivatives.

There are three types of opiate alkaloids. First, the poppy alkaloids: morphine, codeine, thebaine, noscapine and papaverine; then, the semi-synthetic and synthetic derivatives used in therapy as antitussives and analgesics, such as pholcodine, ethylmorphine and dextromethorphan; at last narcotic compounds, diacetylmorphine (heroin) and opiates employed as substitutes in treatment of addiction: buprenorphine and methadone. For classical thin-layer chromatography (TLC) of opium alkaloids, it is necessary to use complex eluents with strong alkaline substances to obtain a clean separation between morphinan and isoquinoline compounds. This study purposes the planar chromatographic analysis of these substances by the automated multiple development (AMD) compared with results obtained by classical TLC method. The aim of this work was to achieve the best separation of these opiate alkaloids and derivatives by this modern technique of planar chromatography. The AMD system provided a clean separation for each of three opiates groups studied and the best results have been obtained with universal gradient: methanol 100, methanol-dichloromethane 50/50, dichloromethane 100, dichloromethane 100, hexane 100 for opium alkaloids and with gradient A: 5% of 28% ammonia in methanol 100, acetone 100, acetone 100, ethyl acetate-dichloromethane 50/50, dichloromethane 100 for antitussives and substitutes. Two reagents were used for the detection of alkaloids by spraying: Dragendorff and iodoplatinate reagents. The detection limits with these two reagents were 1 microg for ethylmorphine, thebaine, papaverine, codeine, and 2 microg for morphine and noscapine and other alkaloids.

Antitussive Agents↗
PubMed2005

Induction of apoptosis by carbazole alkaloids isolated from Murraya koenigii.

In the current study, we isolated 10 carbazole alkaloids from the plant species Murraya koenigii (Rutaceae), and examined their effects on the growth of the human leukemia cell line HL-60. Three carbazole alkaloids, mahanine (6), pyrayafoline-D (7) and murrafoline-I (9), showed significant cytotoxicity against HL-60 cells. Fluorescence microscopy with Hoechst 33342 staining revealed that the percentage of apoptotic cells with fragmented nuclei and condensed chromatin was increased in a time-dependent manner after treatment with each alkaloid. Interestingly, each carbazole alkaloid induced the loss of mitochondrial membrane potential. In addition, both caspase-9 and caspase-3 were also time-dependently activated upon treatment with the alkaloids. Caspase-9 and caspase-3 inhibitors suppressed apoptosis induced by these alkaloids. The results suggest that these three alkaloids induced apoptosis in HL-60 cells through activation of the caspase-9/caspase-3 pathway, through mitochondrial dysfunction.

Apoptosis↗
PubMed2000

The influence of different biotic and abiotic elicitors on the production and profile of tropane alkaloids in hairy root cultures of Brugmansia candida.

Hairy root cultures of Brugmansia candida produce the tropane alkaloids scopolamine and hyoscyamine. In an attempt to increase productivity, several biotic and abiotic elicitors were tested. Salicylic acid increased significantly the release of both alkaloids (2- to 12-fold) and it also acted positively on specific production without altering the production profile. AgNO(3) increased significantly scopolamine release (3-fold) and both alkaloid's accumulation (5- to 8-fold) in the roots, thus favoring the production of scopolamine (up to 2-fold). The inhibiting effects of AgNO(3) and salicylic acid on ethylene could be partly responsible for these responses. Yeast extract incremented the intracellular content of both alkaloids (ca. 3-fold), but particularly increased the release of scopolamine (7-fold). CaCl(2) had little effect on accumulation or release of either alkaloid. CdCl(2) acted positively on the release of both alkaloids (3- to 24-fold), but was highly detrimental to growth. Hairy roots of B. candida are therefore susceptible to elicitation by biotic and abiotic elicitors, with variations in the kinetics of induction and the extent of release of each metabolite, thereby also exerting different effects on the alkaloid profile.

Journal Article↗
PubMed1998

Determination of Aconitum alkaloids in blood and urine samples. II. Capillary liquid chromatographic-frit fast atom bombardment mass spectrometric analysis.

Determination of fourteen alkaloids, toxic Aconitum alkaloids, aconitine, mesaconitine, jesaconitine, hypaconitine and deoxyaconitine, and their hydrolysis products, benzoylaconines and aconines, have been established using capillary liquid chromatography (LC) fast atom bombardment mass spectrometry (FAB-MS) with a frit interface. Protonated molecular ions were observed as base peaks in the FAB-MS for these fourteen alkaloids. All the alkaloids were simultaneously quantified with linear gradient LC elution by solvent mixture of acetonitrile and 0.3% trifluoroacetic acid using selected ion monitoring of the protonated molecular ions. The calibration curves of these alkaloids were linear in injection amounts ranging from 5 to 500 pg, and their detection limits were 1 pg per injection (S/N=3). Solid-phase extraction using Sep-Pak Plus PS-1 was also investigated to clean-up and concentrate alkaloids in blood and urine samples, and showed satisfactory recoveries. This capillary LC-frit-FAB-MS method enables determination of low levels of Aconitum alkaloids in blood and urine samples, coupled with solid-phase extraction.

Aconitine↗
PubMed1982

Accumulation of beta-Carboline Alkaloids and Serotonin by Cell Cultures of Peganum harmala L: I. CORRELATION BETWEEN PLANTS AND CELL CULTURES AND INFLUENCE OF MEDIUM CONSTITUENTS.

A number of cell cultures of Peganum harmala were initiated to check for a correlation between the harman alkaloid content of seedlings and cell lines derived therefrom. Despite a poor correlation between callus or suspension culture lines and parent plants, the mean alkaloid contents of strains derived from seedlings with higher alkaloid yields were nevertheless higher than the mean contents of strains derived from low yield plants. Generally, alkaloid accumulation decreased with the numbers of transfers. By permanent visual selection for fluorescent areas of the calluses, however, a mean content of 0.1% harman alkaloids and 0.1% serotonin could be maintained, which was 10 times higher than in unselected callus cultures.The effects of medium constituents on harman alkaloid and serotonin accumulation were measured for a low yielding, faster growing suspension culture strain and a slowly growing, but high yielding cell line. This led to the development of a production medium without 2,4-dichlorophenoxyacetic acid and phosphate, and with Ca, Mg, and nitrate as sole macronutrients. When this production medium was used, the accumulation of harman alkaloids and serotonin was increased from 0.1 to 1% in the low yielding cell line and from 1 to 2% in the high yielding strain.

Journal Article↗
PubMed1994

Influence of alkaloid concentration of tall fescue straw on the nutrition, physiology, and subsequent performance of beef steers.

Two experiments were conducted to evaluate digestion, performance, and physiological responses to Acremonium coenophialum-infected tall fescue straw offered to vary ergovaline concentrations. In Exp. 1, 16 Hereford x Angus ruminally cannulated steers (370 +/- 12 kg BW, mean +/- SE) were blocked by age and BW and, within block, randomly assigned to one of four treatments containing graded concentrations of ergovaline in the diet: 1) 0 ppb, 2) 158 ppb, 3) 317 ppb, and 4) 475 ppb. Alkaloid concentrations were produced using various mixtures of two varieties of tall fescue straw that had similar genetic and phenotypic characteristics but differed in degree of endophyte incidence and associated concentrations of alkaloids. In the 36-d digestion study, feed intake, apparent DMD, and total tract NDF digestion were not influenced by alkaloid concentration (P > .10). Differences were observed with digesta kinetics; specifically indigestible ADF (IADF) fill and outflow decreased linearly with increasing alkaloid concentration (P < .10). These differences, however, may be attributed to differences in IADF concentration of the diets. Physiological variables (heart rates, respiration rates, and rectal, ear, and tailhead skin surface temperatures) were not influenced by alkaloid concentration (P > .10). Concentration of serum prolactin measured weekly tended (P < .10) to decrease with increasing alkaloid concentration of the diet. At the conclusion of the study, each steer was injected with 100 micrograms of thyrotropin-releasing hormone (TRH). All steers responded to the TRH challenge (P < .10); however, responses did not differ (P > .10) between alkaloid concentrations of the basal diet (P > .10).(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Nutritional Physiological Phenomena↗
PubMed1999

[The effect of erycibele alkaloid on intracellular Ca2+ mobilation of cultured human ciliary muscle cells].

PURPOSE: To study the effect of erycibele alkaloid on cultured human ciliary muscle intracellular Ca2+ movement. METHODS: Intracellular Ca2+ was studied by Fura-2 probe and muscarinic antangonist was applied. RESULTS: Erycibele alkaloid had no any possible disturbulance on the examination system. The average resting[Ca2+]i was 79.3 +/- 28.7 nmol/Lol/L (n = 24). Erycibele alkaloid caused biphase [Ca2+]i elevation. Non-selective muscarinic antagonist Atropine (1 nmol/L) could completely block the 1 mumol/L erycibele alkaloid induced [Ca2+]i elevation; M1 antagonist Pirenzipine could not block the 1 mumol/L erycibele alkaloid induced [Ca2+]i elevation in low concentration (0.03 nmol/L) but in higher concentration (1 nmol/L). M3 antagonist 4-diphenyl acetoxy N-methy piperidine methiodide could completely block the 1 mumol/L erycibele alkaloid induced [Ca2+]i elevation in low and high concentration. CONCLUSION: The effect of erycibele alkaloid on increasing cultured human ciliary muscle cell intracellular Ca2+ is mediated by M3 receptor subtype.

Biological Transport, Active↗
PubMed1994

2,4-D and alkaloid accumulation in periwinkle cell suspensions.

Omission of 2,4-D from culture medium during one subculture of Catharanthus roseus cells, strain C20, resulted in an increased alkaloid accumulation, without effect on growth. Alkaloid accumulation, rather than growth, seemed to be more sensitive to 2,4-D. 2,4-D inhibited alkaloid accumulation essentially during growth phase, but its inhibitory effect during this period was partially reversible. As this reversibility was underlined only during the stationary phase, this suggested that this action could be situated upstream in a terpenoid non-specific pathway. 2,4-D feeding showed that inhibition is weaker and weaker as the alkaloid accumulation period proceeds. Auxin action during this period could take place downstream in specific alkaloid pathways. The lower alkaloid accumulation obtained after loganic acid feeding compared to that obtained with secologanin and loganin could indicate that loganic acid methylation should be one of the 2,4-D target(s).

2,4-Dichlorophenoxyacetic Acid↗
PubMed2006

RNA binding small molecules: studies on t-RNA binding by cytotoxic plant alkaloids berberine, palmatine and the comparison to ethidium.

The interaction of two natural protoberberine plant alkaloids berberine and palmatine with t-RNA(phe) was studied using various biophysical techniques and the data was compared with the binding of the classical DNA intercalator, ethidium. The results of optical thermal melting, differential scanning calorimetry and circular dichroism characterized the native cloverleaf structure of t-RNA under the conditions of the study. The strong binding of the alkaloids and ethidium to t-RNA was revealed from the absorption and fluorescence studies. The salt dependence of the binding constants enabled the dissection of the binding free energy to electrostatic and non-electrostatic contributions. This analysis revealed a surprisingly large favourable component of the non-electrostatic contribution to the binding of these charged alkaloids and ethidium to t-RNA. Isothermal titration calorimetric studies revealed that the binding of both the alkaloids is driven by a moderately favourable enthalpy decrease and a moderately favourable entropy increase while that of ethidium is driven by a large favourable enthalpy decrease. Taken together, the results suggest that the binding of these alkaloid molecules on the t-RNA structure appears to be mostly by partial intercalation while ethidium intercalates to the t-RNA. These results reveal the molecular aspects on the interaction of these alkaloids to t-RNA.

Alkaloids↗
PubMed2004

Structural analyses of protoberberine alkaloids in medicine herbs by using ESI-FT-ICR-MS and HPLC-ESI-MS(n).

The Electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS) using sustained off-resonance irradiation (SORI)/collision-induced dissociation (CID) method at high mass resolution has been first applied to investigate the characteristic fragment ions of four protoberberine alkaloids in medicine herbs. The ESI-FT-ICR SORI-CID experiment results demonstrate that the unambiguous elemental composition of fragment ions can be obtained at high mass resolution, then the logical fragmentation pathways of the protoberberine alkaloids has been proposed. The characteristic fragment ions of CID and MS(n) of protoberberine alkaloids have been discussed, which are specific and useful for the identification of some protoberberine alkaloid compounds. Then, the extracts of four kinds of medicine herbs have been analyzed by HPLC-ESI-MS(n). According to these characteristic fragmentation pathways, the retention time (t(R)) of HPLC and mass spectra of product ion, the structures of six kinds of protoberberine alkaloids have been identified. And, in the present paper, the selected ion monitoring (SIM) method has been used to separate and identify the alkaloid isomers.

Alkaloids↗
PubMed2006

Oxindole alkaloids from Uncaria tomentosa induce apoptosis in proliferating, G0/G1-arrested and bcl-2-expressing acute lymphoblastic leukaemia cells.

Natural products are still an untapped source of promising lead compounds for the generation of antineoplastic drugs. Here, we investigated for the first time the antiproliferative and apoptotic effects of highly purified oxindole alkaloids, namely isopteropodine (A1), pteropodine (A2), isomitraphylline (A3), uncarine F (A4) and mitraphylline (A5) obtained from Uncaria tomentosa, a South American Rubiaceae, on human lymphoblastic leukaemia T cells (CCRF-CEM-C7H2). Four of the five tested alkaloids inhibited proliferation of acute lymphoblastic leukaemia cells. Furthermore, the antiproliferative effect of the most potent alkaloids pteropodine (A2) and uncarine F (A4) correlated with induction of apoptosis. After 48 h, 100 micromol/l A2 or A4 increased apoptotic cells by 57%. CEM-C7H2 sublines with tetracycline-regulated expression of bcl-2, p16ink4A or constitutively expressing the cowpox virus protein crm-A were used for further studies of the apoptosis-inducing properties of these alkaloids. Neither overexpression of bcl-2 or crm-A nor cell-cycle arrest in G0/G1 phase by tetracycline-regulated expression of p16INK4A could prevent alkaloid-induced apoptosis. Our results show the strong apoptotic effects of pteropodine and uncarine F on acute leukaemic lymphoblasts and recommend the alkaloids for further studies in xenograft models.

Alkaloids↗
PubMed1989

Reactivity of dorsal pedal vein of cattle to selected alkaloids associated with Acremonium coenophialum-infected fescue grass.

We determined the vasoconstrictive effects of selected ergot alkaloids, and a sample containing loline and its derivative alkaloids, on the isolated dorsal pedal vein of cattle, as a model system to study one of the toxic effects that result from cattle ingesting fescue forage infected with the endophytic fungus Acremonium coenophilalum. The ergot compounds ergotamine, ergosine, and agroclavine constricted this peripheral vein of cattle, but much less so than did the alpha-adrenergic agonist norepinephrine, which supports the ergots acting as partial agonists for these receptors. However, the sample of loline and loline-derivative alkaloids did not affect the dorsal pedal vein when given at concentrations similar to those of the ergot compounds. Loline and loline-derivative alkaloid sample at high concentrations partially inhibited norepinephrine-elicited vascular contraction, an effect that appeared to be unrelated to alpha-adrenoceptor activity. Thus, in the dorsal pedal vein model in cattle, the ergopeptide alkaloids were more venoconstrictive than were loline and its derivative alkaloids.

Acremonium↗
PubMed1996

Enzymology of indole alkaloid biosynthesis in Catharanthus roseus.

Indole alkaloids in Catharanthus roseus have been in focus because of their medicinal value. These alkaloids consist of an indole moiety provided by tryptamine and a terpenoid portion provided by the secologanin. The most important catharanthus alkaloids are vinblastine (VLB), vincristine (VCR) and ajmalicine. VLB and VCR are clinically useful anticancer agents whereas ajmalicine is used for the treatment of circulatory diseases. VCR and VLB are the most expensive because of their low abundance in the plant, and are formed by the coupling of monomeric indole alkaloids vindoline and catharanthine, catalysed by peroxidases. The pathway that lead to monomeric indole alkaloids involves more than 20 enzymes of which 16 enzymes have been isolated and characterized biochemically, and only three at the molecular level. The present state of knowledge on enzymes and genes involved in indole alkaloid biosynthesis and various aspects of their regulation has been discussed.

Alkaloids↗