Ibogaine Abstracts on PubMed

18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action.

18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action. 18-MC, a novel iboga alkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18-MC ameliorate opioid withdrawal signs. Both ibogaine and 18-MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine-induced increases in accumbal dopamine. Both ibogaine and 18-MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18-MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine-induced locomotion in morphine-experienced rats. Ibogaine produces whole body tremors and, at high doses (> or = 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, decreases heart rate at high doses. While 18-MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18-MC has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. The data suggest that 18-MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11085336&dopt=Abstract
Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures.

Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures. Ibogaine is an indole alkaloid found in the roots of Tabernanthe Iboga (Apocynaceae family), a rain forest shrub that is native to western Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and thirst, and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and opiates. Anecdotal reports attest that a single dose of ibogaine eliminates opiate withdrawal symptoms and reduces drug craving for extended periods of time. The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. The majority of ibogaine biotransformation proceeds via CYP2D6, including the O-demethylation of ibogaine to 12-hydroxyibogamine (noribogaine). Blood concentration-time effect profiles of ibogaine and noribogaine obtained for individual subjects after single oral dose administrations demonstrate complex pharmacokinetic profiles. Ibogaine has shown preliminary efficacy for opiate detoxification and for short-term stabilization of drug-dependent persons as they prepare to enter substance abuse treatment. We report here that ibogaine significantly decreased craving for cocaine and heroin during inpatient detoxification. Self-reports of depressive symptoms were also significantly lower after ibogaine treatment and at 30 days after program discharge. Because ibogaine is cleared rapidly from the blood, the beneficial aftereffects of the drug on craving and depressed mood may be related to the effects of noribogaine on the central nervous system.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11085338&dopt=Abstract
Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption.

Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption. Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15659598&dopt=Abstract

Drug discrimination studies with ibogaine.

Drug discrimination studies with ibogaine. The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT2A, 5-HT2C, and sigma 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not appear to play a major role. Ibogaine’s hallucinogenic effects may be explained by its interactions with 5-HT2A and 5-HT2C receptors, while its putative antiaddictive properties may result from its interactions with sigma 2 and opiate receptors. Alternatively, the possibility that ibogaine’s hallucinogenic properties underlie its antiaddictive effects, as previously suggested (34), would support a role for 5-HT2 receptors in mediating the reported therapeutic effects of ibogaine. Certainly many questions remain regarding ibogaine’s mechanism of action. Although drug discrimination will be useful for answering some of those questions, the true potential of this technique is realized whin it is combined with other techniques. The next few years promise to be fruitful with respect to our understanding of this agent. Reasons supporting this belief include advances in the study of sigma receptors, interest in ibogaine’s effects on second messenger systems, and the development of ibogaine congeners such as 18-methoxycoronaridine (35). In conclusion, the aforementioned studies should serve to guide further endeavors. Pertinent questions have been generated: What is the role of sigma receptors in the effects of ibogaine, especially with regard to addiction? How does ibogaine affect opiate neurotransmission? What effects, if any, do the Harmala alkaloids have on addiction phenomena? What is the mechanism of action of harmaline? Can 10-hydroxyibogamine serve as a discriminative stimulus and, if so, what receptor interactions mediate its stimulus effects? Does the ibogaine-trained stimulus generalize to novel agents, including 18-methoxycoronaridine?

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705117&dopt=Abstract

Comparative neurobiological effects of ibogaine and MK-801 in rats.

Comparative neurobiological effects of ibogaine and MK-801 in rats. Ibogaine is a plant-derived alkaloid with putative ‘anti-addictive’ properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an N-methyl-D-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (N=6-8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=10891627&dopt=Abstract

Ibogaine alters synaptosomal and glial glutamate release and uptake.

Ibogaine alters synaptosomal and glial glutamate release and uptake. Ibogaine has aroused expectations as a potentially innovative medication for drug addiction. It has been proposed that antagonism of the NMDA receptor by ibogaine may be one of the mechanisms underlying its antiaddictive properties; glutamate has also been implicated in ibogaine-induced neurotoxicity. We here report the effects of ibogaine on [3H]glutamate release and uptake in cortical and cerebellar synaptosomes, as well as in cortical astrocyte cultures, from mice and rats. Ibogaine (2-1000 microM) had no effects on glutamate uptake or release by rat synaptosomes. However, ibogaine (500-1000 microM) significantly inhibited the glutamate uptake and stimulated the release of glutamate by cortical (but not cerebellar) synaptosomes of mice. In addition, ibogaine (1000 microM) nearly abolished glutamate uptake by cortical astrocyte cultures from rats and mice. The data provide direct evidence of glutamate involvement in ibogaine-induced neurotoxicity.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11209932&dopt=Abstract

Long-lasting ibogaine protection against NMDA-induced convulsions in mice.

Long-lasting ibogaine protection against NMDA-induced convulsions in mice. Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30 min, 24, 48, and 72 h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30 min or 48 h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11055745&dopt=Abstract

Combating substance abuse with ibogaine: pre- and posttreatment recommendations and an example of successive model fitting analyses.

Combating substance abuse with ibogaine: pre- and posttreatment recommendations and an example of successive model fitting analyses. Ibogaine is an indole alkaloid derived from the root bark of the African shrub Tabernan the iboga and it has been used for many years as a medicinal and ceremonial agent in West Central Africa. Furthermore, both anecdotal observations and recent studies suggest that ibogaine alleviates withdrawal symptoms and reduces drug cravings. Although ibogaine articles typically include information bearing on the duration of drug abstinence following treatment, little if any attention is given to the psychological and environmental factors that might facilitate a positive treatment outcome. Hence, a major purpose of the present review is to suggest a number of theory-driven, pretreatment and posttreatment recommendations that have good potential for enhancing ibogaine’s effectiveness. The second major purpose of this review is to demonstrate, through a reanalysis of previously published results, the utility of conducting successive model fitting analyses on ibogaine treatment data. Such analyses are useful for determining both the strength and form of the association between pre-ibogaine treatment variables and post-ibogaine treatment outcomes. Finally, in order to facilitate future quantitative reviews, the authors recommend that a minimum set of patient- and treatment-related variables be included in all ibogaine publications involving human participants.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15369200&dopt=Abstract

Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats.

Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats. Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for addiction to opioids and other drugs of abuse. The mechanism for its putative anti-addictive effects is unknown. In this study, the effects of ibogaine on local cerebral glucose utilization (LCGU) were determined in freely moving, drug-naive, or morphine-dependent adult, male, Sprague-Dawley rats using the [(14)C]2-deoxyglucose (2-DG) method. Morphine-dependent rats were treated with increasing doses of morphine (5-25 mg/kg, s.c., b.i.d.) and then maintained at 25 mg/kg (b.i.d.) for 4-7 days. For the 2-DG procedure, rats were injected with saline or ibogaine (40 mg/kg, i.p.). 2-DG was administered 1 h after administration of ibogaine. The rate of LCGU was determined by quantitative autoradiography in 46 brain regions. In drug-naive animals, ibogaine produced significant increases in LCGU in the parietal, cingulate, and occipital cortices and cerebellum compared to controls consistent with its activity as a hallucinogen and a tremorogen. Morphine-dependent rats had only minor alterations in LCGU at the time assessed in this experiment. However, in morphine-dependent animals, ibogaine produced a global decrease in LCGU that was greatest in brain regions such as the lateral and medial preoptic areas, nucleus of the diagonal band, nucleus accumbens shell, inferior colliculus, locus coeruleus, and flocculus compared to morphine-dependent animals treated with saline. These findings indicate that ibogaine produces distinctly different effects on LCGU in drug-naive and morphine-dependent rats. This suggests that different mechanisms may underlie ibogaine’s hallucinogenic and anti-addictive effects.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15019575&dopt=Abstract

Administration of a non-NMDA antagonist, GYKI 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine.

Administration of a non-NMDA antagonist, GYKI 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine. Ibogaine is a tremorigenic hallucinogen that has been proposed for clinical use in treating addiction. We previously reported that ibogaine, administered systemically, produces degeneration of a subset of Purkinje cells in the cerebellum, primarily within the vermis. Ablation of the inferior olive affords protection against ibogaine-induced neurotoxicity leading to the interpretation that ibogaine itself is not directly toxic to Purkinje cells. We postulated that ibogaine produces sustained excitation of inferior olivary neurons that leads to excessive glutamate release at climbing fiber terminals, causing subsequent excitotoxic injury to Purkinje cells. The neuronal degeneration induced by ibogaine provides an animal model for studying excitotoxic injury in order to analyze the contribution of glutamate receptors to this injury and to evaluate neuroprotective strategies. Since non-N-methyl-D-aspartate (NMDA) receptors mediate Purkinje cell excitation by climbing fibers, we hypothesized that 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-52466), which antagonizes non-NMDA receptors, may have a neuroprotective effect by blocking glutamatergic excitation at climbing fiber synapses. To test this hypothesis, rats were administered systemic ibogaine plus GYKI-52466 and the degree of neuronal injury was analyzed in cerebellar sections. The results indicate that the AMPA antagonist GYKI-52466 (10 mg/kg i.p. x 3) does not protect against Purkinje cell injury at the doses used. Rather, co-administration of GYKI-52466 with ibogaine produces increased toxicity evidenced by more extensive Purkinje cell degeneration. Several hypotheses that may underlie this result are discussed. Although the reason for the increased toxicity found in this study is not fully explained, the present results show that a non-NMDA antagonist can produce increased excitotoxic injury under some conditions. Therefore, caution should be exercised before employing glutamate antagonists to reduce the risk of neuronal damage in human clinical disorders. Moreover, the contribution of different glutamate receptors to excitotoxic injury is complex and merits further analysis.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15262328&dopt=Abstract

Ibogaine interferes with motivational and somatic effects of naloxone-precipitated withdrawal from acutely administered morphine.

Ibogaine interferes with motivational and somatic effects of naloxone-precipitated withdrawal from acutely administered morphine. It has been reported that ibogaine interferes with somatic withdrawal reactions in rats chronically treated with morphine. The present experiments demonstrated that ibogaine also interferes with motivational withdrawal reactions and somatic withdrawal reactions in rats treated with morphine on only two occasions. On each of two conditioning trials, naloxone was administered 24 h following an injection of morphine. Four hours prior to each naloxone administration, rats were injected with either ibogaine or saline. In two experiments, ibogaine interfered with naloxone-precipitated withdrawal. In Experiment 1, ibogaine-treated rats displayed a weaker aversion to the withdrawal-paired chamber, and in Experiment 2, ibogaine-treated rats displayed fewer somatic withdrawal reactions than did saline treated rats.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11817506&dopt=Abstract

Liquid chromatography-electrospray mass spectrometry determination of ibogaine and noribogaine in human plasma and whole blood. Application to a poisoning involving Tabernanthe iboga root.

Liquid chromatography-electrospray mass spectrometry determination of ibogaine and noribogaine in human plasma and whole blood. Application to a poisoning involving Tabernanthe iboga root. A liquid chromatography/electrospray ionization mass spectrometry (LC-ESI-MS) method was developed for the first time for the determination of ibogaine and noribogaine in human plasma and whole blood. The method involved solid phase extraction of the compounds and the internal standard (fluorescein) from the two matrices using OasisHLB columns. LC separation was performed on a Zorbax eclipse XD8 C8 column (5 microm) with a mobile phase of acetonitrile containing 0.02% (v/v) trimethylamine and 2mM ammonium formate buffer. MS data were acquired in single ion monitoring mode at m/z 311.2, 297.2 and 332.5 for ibogaine, noribogaine and fluorescein, respectively. The drug/internal standard peak area ratios were linked via a quadratic relationship to plasma (0.89-179 microg/l for ibogaine; 1-200 microg/l for noribogaine) and to whole blood concentrations (1.78-358 microg/kg for ibogaine; 2-400 microg/kg for noribogaine). Precision ranged from 4.5 to 13% and accuracy was 89-102%. Dilution of the samples had no influence on the performance of the method. Extraction recoveries were > or =94% in plasma and > or =57% in whole blood. The lower limits of quantitation were 0.89 microg/l for ibogaine and 1 microg/l for noribogaine in plasma, and 1.78 microg/kg for ibogaine and 2 microg/kg for noribogaine in whole blood. In frozen plasma samples, the two drugs were stable for at least 1 year. In blood, ibogaine and noribogaine were stable for 4h at 4 degrees C and 20 degrees C and 2 months at -20 degrees C. The method was successfully used for the analysis of a poisoning involving Tabernanthe iboga root.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16798116&dopt=Abstract

Ibogaine reduces organ colonization in murine systemic and gastrointestinal Candida albicans infections.

Ibogaine reduces organ colonization in murine systemic and gastrointestinal Candida albicans infections. In the present study the effect of the indole alkaloid ibogaine on the in vitro lipolytic activity and adherence to epithelial cells of Candida albicans was investigated. The substance was administered intraperitoneally at a dose of 5 mg kg(-1) day(-1) in mice with disseminated and gastrointestinal C. albicans infections. Ibogaine significantly decreased the rate of mortality and the number of C. albicans c.f.u. recovered from the kidney, liver and spleen. Ibogaine interfered with the early stages of both disseminated and gastrointestinal C. albicans infections but did not reduce the number of C. albicans c.f.u. in the organs at the late phase of infections. The development of a specific immune response was not influenced by ibogaine, since the delayed-type hypersensitivity reaction to C. albicans and the production of interferon (IFN)-gamma were similar in control and ibogaine-treated mice. The combined use of amphotericin B plus ibogaine in the treatment of mice with gastrointestinal infection reduced organ colonization more strongly than each substance alone.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15947429&dopt=Abstract

The development and expression of locomotor sensitization to nicotine in the presence of ibogaine.

The development and expression of locomotor sensitization to nicotine in the presence of ibogaine. Ibogaine is a naturally occurring psychoactive alkaloid with claimed efficacy in the treatment of certain drug addictions, including nicotine. It has been reported to be a non-competitive blocker of nicotinic receptors, with a potent inhibitory action on nicotinic acetylcholine receptor-mediated catecholamine release. We have investigated the effect of different doses of ibogaine on the development and expression of sensitization to the locomotor stimulant effect of nicotine in rats, a facilitatory process in which a history of exposure to nicotine results in enhanced locomotor activity when the same dose of nicotine is administered repeatedly. The effects were determined of co-administering ibogaine (0.0, 5.0 or 10 mg/kg i.p.) with nicotine (0.0 or 0.4 mg/kg s.c.) daily for 21 days. Dose-response curves for nicotine (0.04-0.8 mg/kg s.c.) were then determined in groups of 10 rats. There was clear sensitization of the locomotor activity produced by nicotine in photocell activity cages but co-administration of ibogaine with nicotine had no effect on the degree of sensitization. Ibogaine (5-20 mg/kg) itself did not influence locomotor activity and was also without effect on the expression of the sensitized response to 0.4 mg/kg of nicotine (n = 10). Thus, there was no evidence that ibogaine may retard or suppress sensitization to nicotine.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11103895&dopt=Abstract

Distribution of ibogaine and noribogaine in a man following a poisoning involving root bark of the Tabernanthe iboga shrub.

Distribution of ibogaine and noribogaine in a man following a poisoning involving root bark of the Tabernanthe iboga shrub. In the present paper, we report for the first time the tissue distribution of ibogaine and noribogaine, the main metabolite of ibogaine, in a 48-year-old Caucasian male, with a history of drug abuse, found dead at his home after a poisoning involving the ingestion of root bark from the shrub Tabernanthe iboga. Ibogaine and noribogaine were quantified in tissues and fluids using a fully validated liquid chromatography-electrospray mass spectrometry method. Apart from cardiac tissue, ibogaine and noribogaine were identified in all matrices investigated. The highest concentrations were found in spleen, liver, brain, and lung. The tissue/subclavian blood concentration ratios averaged 1.78, 3.75, 1.16, and 4.64 for ibogaine and 0.83, 2.43, 0.90, and 2.69 for noribogaine for spleen, liver, brain, and lung, respectively. Very low concentrations of the two drugs were found in the prostatic tissue. Both ibogaine and noribogaine are secreted in the bile and cross the blood-brain barrier. Four other compounds were detected in most of the studied matrices. One of them was identified as ibogamine. Unfortunately, we were not able to positively identify the other three compounds because of the unavailability of reference substances. Two of them could possibly be attributed to the following oxidation products: iboluteine and desmethoxyiboluteine. The third compound could be ibogaline.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16959135&dopt=Abstract

Differential effects of ibogaine on behavioural and dopamine sensitization to cocaine.

Differential effects of ibogaine on behavioural and dopamine sensitization to cocaine. To investigate a possible basis for the proposed anti-addictive property of ibogaine, the effects of ibogaine (40 mg/kg, i.p., 19 h earlier) on the expression of sensitization induced by cocaine were investigated. Ibogaine pretreatment potentiated the increase in the stereotypic effects of a cocaine challenge (20 mg/kg) in both sensitized (5 x 15 mg/kg, i.p.) and acutely treated rats. However, while ibogaine pretreatment did not significantly alter the dopamine response in the nucleus accumbens to acute cocaine, it abolished the expression of cocaine-induced dopamine sensitization. This result demonstrates that ibogaine pretreatment can reverse one of the neuroadaptations produced by chronic cocaine administration, an effect that may contribute to its putative anti-addictive property.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=10854838&dopt=Abstract

Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasmic-facing form of the transporter.

Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasmic-facing form of the transporter. Ibogaine, a hallucinogenic alkaloid with purported anti-addiction properties, inhibited serotonin transporter (SERT) non-competitively by decreasing Vmax with little change in the Km for serotonin (5-HT). Ibogaine also inhibited binding to SERT of the cocaine analog beta-CIT (2beta-2-carbomethoxy-3-(4-[125I]iodophenyl)tropane). However, inhibition of binding was competitive, increasing the apparent Kd without much change in Bmax. Ibogaine increased the reactivity of cysteine residues positioned in the proposed cytoplasmic permeation pathway of SERT but not at nearby positions out of that pathway. In contrast, cysteines placed at positions in the extracellular permeation pathway reacted at slower rates in the presence of ibogaine. These results are consistent with the proposal that ibogaine binds to, and stabilizes, the form of SERT from which 5-HT dissociates to the cytoplasm, in contrast with cocaine, which stabilizes the form that binds extracellular 5-HT.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=17698848&dopt=Abstract

Ibogaine affects brain energy metabolism.

Ibogaine affects brain energy metabolism. Ibogaine is an indole alkaloid present in the root of the plant Tabernanthe iboga. It is known to attenuate abstinence syndrome in animal models of drug addiction. Since the anti-addiction effect lasts longer than the presence of ibogaine in the body, some profound metabolic changes are expected. The aim of this study was to investigate the effect of ibogaine on protein expression in rat brains. Rats were treated with ibogaine at 20 mg/kg body weight i.p. and subsequently examined at 24 and 72 h. Proteins were extracted from whole brain and separated by two-dimensional (2-D) electrophoresis. Individual proteins were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). Enzymes of glycolysis and tricarboxylic acid (TCA) cycle namely glyceraldehyde-3-phosphate dehydrogenase, aldolase A, pyruvate kinase and malate dehydrogenase were induced. The results suggest that the remedial effect of ibogaine could be mediated by the change in energy availability. Since energy dissipating detoxification and reversion of tolerance to different drugs of abuse requires underlying functional and structural changes in the cell, higher metabolic turnover would be favourable. Understanding the pharmacodynamics of anti-addiction drugs highlights the subcellular aspects of addiction diseases, in addition to neurological and psychological perspectives.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=17054944&dopt=Abstract

Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, Ibogaine.

Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, Ibogaine. We recently showed that the up-regulation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the midbrain, is the molecular mechanism by which the putative anti-addiction drug Ibogaine mediates its desirable action of reducing alcohol consumption. Human reports and studies in rodents have shown that a single administration of Ibogaine results in a long-lasting reduction of drug craving (humans) and drug and alcohol intake (rodents). Here we determine whether, and how, Ibogaine exerts its long-lasting actions on GDNF expression and signaling. Using the dopaminergic-like SHSY5Y cell line as a culture model, we observed that short-term Ibogaine exposure results in a sustained increase in GDNF expression that is mediated via the induction of a long-lasting autoregulatory cycle by which GDNF positively regulates its own expression. We show that the initial exposure of cells to Ibogaine or GDNF results in an increase in GDNF mRNA, leading to protein expression and to the corresponding activation of the GDNF signaling pathway. This, in turn, leads to a further increase in the mRNA level of the growth factor. The identification of a GDNF-mediated, autoregulatory long-lasting feedback loop could have important implications for GDNF’s potential value as a treatment for addiction and neurodegenerative diseases.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=17023388&dopt=Abstract

Fatalities after taking ibogaine in addiction treatment could be related to sudden cardiac death caused by autonomic dysfunction.

Fatalities after taking ibogaine in addiction treatment could be related to sudden cardiac death caused by autonomic dysfunction. Ibogaine is the most important alkaloid of the Central African Iboga-shrub. It is the central drug in Gabonian initiation ceremonies in which it is used to cause a near-death experience. In Western countries it is used in private clinics to treat addiction. However, in the United States and most European countries it is classified as an illegal drug because at least eight persons have died after having taken Ibogaine. These fatalities occurred in most cases several days after ingestion or following the intake of very small doses. There is no conclusive explanation at the present time for these deaths. We hypothesize, that these deaths may be a result of cardiac arrhythmias, caused by a dysregulation of the autonomic nervous system. Ibogaine affects the autonomic nervous system by influencing several neurotransmitter-systems and the fastigial nucleus. The cerebellar nucleus responds to small doses with a stimulation of the sympathetic system, leading to a fight or flight reaction. High doses, however, lead to a vagal dominance: a “feigned death”. The risk of cardiac arrhythmias is increased in situations of sympathetic stimulation or coincidence of a high parasympathetic tonus and a left-sided sympathetic stimulation. This could occur under influence of small doses of ibogaine and also at times of exhaustion with a high vagal tonus, when sudden fear reactions could cause a critical left-sided sympathetic stimulation. Gabonian healers prevent these risks by isolating their patients from normal life and by inducing a trance-state with right-hemispheric and vagal dominance for several days.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16698188&dopt=Abstract

Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation.

Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation. The mapping of the human genetic code will enable us to identify potential gene products involved in human addictions and diseases that have hereditary components. Thus, large-scale, parallel gene-expression studies, made possible by advances in microarray technologies, have shown insights into the connection between specific genes, or sets of genes, and human diseases. The compulsive use of addictive substances despite adverse consequences continues to affect society, and the science underlying these addictions in general is intensively studied. Pharmacological treatment of drug and alcohol addiction has largely been disappointing, and new therapeutic targets and hypotheses are needed. As the usefulness of the pharmacotherapy of addiction has been limited, an emerging potential, yet controversial, therapeutic agent is the natural alkaloid ibogaine. We have continued to investigate programs of gene expression and the putative signaling molecules used by psychostimulants such as amphetamine in in vivo and in vitro models. Our work and that of others reveal that complex but defined signal transduction pathways are associated with psychostimulant administration and that there is broad-spectrum regulation of these signals by ibogaine. We report that the actions of methamphetamine were similar to those of cocaine, including the propensity to alter long-term potentiation (LTP) in the hippocampus of the rat brain. This action suggests that there may be a “threshold” beyond which the excessive brain stimulation that probably occurs with compulsive psychostimulant use results in the occlusion of LTP. The influence of ibogaine on immediate early genes (IEGs) and other candidate genes possibly regulated by psychostimulants and other abused substances requires further evaluation in compulsive use, reward, relapse, tolerance, craving and withdrawal reactions. It is therefore tempting to suggest that ibogaine signals addiction gene products.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12105083&dopt=Abstract

Plant derivatives in the treatment of alcohol dependency.

The present review summarizes the findings of the effects of extracts of purified compounds from several plants on alcohol intake in alcohol-preferring rats. These include St. John’s wort (Hypericum perforatum, HPE), kudzu (Pueraria lobata) and ibogaine (Tabernanthe iboga). Alcohol-preferring (P), Marchigian Sardinian (msP), high-alcohol-drinking (HAD), Fawn-Hooded (FH) rats were allowed to drink alcohol or water voluntarily to establish baseline levels. Pure compounds (puerarin, daidzin, daidzein or analogs) isolated from kudzu, extracts from HPE or ibogaine and its analog were given by either intraperitoneal or oral administration. After acute administration, all agents dose-dependently reduced alcohol intake with minimal effects on food intake. Puerarin and HPE were also effective following chronic treatment. Overall, it is clear that pure compounds (daidzin, puerarin), extracts from St. John’s wort, ibogaine and an ibogaine analog suppress alcohol intake in animal models of excessive drinking with minimal effects on other appetitive behaviors. Although the true mechanisms of action of these compounds on alcohol intake are not fully understood, with the current information, it appears that these compounds exert their effects by modulating several neuronal systems implicated in drinking behavior. However, their role in the future of pharmacotherapy for alcoholism will depend upon the outcome of carefully conducted clinical trials.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12895677&dopt=Abstract

Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration.

The iboga alkaloid ibogaine and the novel iboga alkaloid congener 18-methoxycoronaridine are putative anti-addictive agents. Using patch-clamp methodology, the actions of ibogaine and 18-methoxycoronaridine at various neurotransmitter receptor ion-channel subtypes were determined. Both ibogaine and 18-methoxycoronaridine were antagonists at alpha 3 beta 4 nicotinic receptors and both agents were more potent at this site than at alpha 4 beta 2 nicotinic receptors or at NMDA or 5-HT(3) receptors; 18-methoxycoronaridine was more selective in this regard than ibogaine. In studies of morphine and methamphetamine self-administration, the effects of low dose combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan and of mecamylamine with dextromethorphan were assessed. Mecamylamine and dextromethorphan have also been shown to be antagonists at alpha 3 beta 4 nicotinic receptors. All three drug combinations decreased both morphine and methamphetamine self-administration at doses that were ineffective if administered alone. The data are consistent with the hypothesis that antagonism at alpha 3 beta 4 receptors is a potential mechanism to modulate drug seeking behavior. 18-Methoxycoronaridine apparently has greater selectivity for this site than other agents and may be the first of a new class of synthetic agents acting via this novel mechanism to produce a broad spectrum of anti-addictive activity.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11906717&dopt=Abstract

Iboga interactions with psychomotor stimulants: panacea in the paradox?

Currently, no effective therapy has been approved for the treatment of addiction to stimulant drugs (e.g., cocaine, amphetamine and its methylated derivatives). However, preclinical studies indicate that the naturally-occurring indole alkaloid, ibogaine, and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), attenuate stimulant self-administration in laboratory animals. The in vivo pharmacological interactions between iboga agents and stimulant drugs are unclear. Ibogaine enhances the increase in accumbal dopamine produced by the acute administration of stimulant drugs. Consistent with these data, both ibogaine and 18-MC potentiate the expression of stimulant-induced motor behaviors in acute and chronic stimulant-treated animals. To account for the paradox between their effects on self-administration and motor behavior, we proposed that iboga agents interfere with stimulant self-administration by increasing sensitivity to their psychomotor-activating effects. However, this interpretation is contradicted by very recent observations that 18-MC is without effect on the dopamine response to acute cocaine and that both ibogaine and 18-MC block the expression of sensitized levels of dopamine in the nucleus accumbens produced by chronic cocaine administration. Thus, a positive relationship exists between the effects of iboga pretreatment on stimulant-induced dopamine sensitization and stimulant self-administration behavior. These data indicate that iboga agents might attenuate stimulant self-administration by reversing the neuroadaptations theoretically implicated in drug craving and compulsive drug-seeking behavior.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=10936624&dopt=Abstract

Ibogaine–the substance for treatment of toxicomania. Neurochemical and pharmacological action.

[Ibogaine–the substance for treatment of toxicomania. Neurochemical and pharmacological action] The review of scientific literature, concerning the indol alkaloid Ibogaine, which is extracted from the bush Tabernanthe Iboga, is presented in this article. Used as a stimulating factor for hundred of years in non-traditional medicine, this alkaloid could be important for modern pharmacology because of potential anti-addictive properties. The mechanism of action of this alkaloid is closely related to different neurotransmitting systems. Studies with animals allow concluding that Ibogaine or medicines based on this alkaloid can be used for treatment of drug dependencies.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15064541&dopt=Abstract

Quantitation of ibogaine and 12-hydroxyibogamine in human plasma by liquid chromatography with fluorimetric detection.

Quantitation of ibogaine and 12-hydroxyibogamine in human plasma by liquid chromatography with fluorimetric detection. A high-performance liquid chromatographic (HPLC) method with fluorimetric detection was developed for the simultaneous determination of ibogaine and noribogaine in human plasma using fluorescein as internal standard. This method involved a solid phase extraction of the compounds from plasma using N-vinylpyrrolidone-divinybenzene copolymer cartridges. Separation of the three analytes was performed on a reversed-phase Supelcosil C18 analytical column (75 mm x 4.6mm i.d., 3 microm particle size). The excitation wavelength was set at 230 nm for the first 15.8min and then at 440 nm for the following 14.2 min; the emission wavelength was set at 336 nm for the first 15.8 min and then at 514 nm for the following 14.2 min. Obtained from the method validation, inter-assay precision was 6.0-12.5% and accuracy was 95.4-104%. The extraction efficiencies of the assay were higher than 94% and were constant across the calibration range. The lower limits of quantitation were 0.89 ng/ml for ibogaine and 1 ng/ml for noribogaine; at these levels, precision was < or =17% and accuracy was 95-105%. In this paper, extensive stability testing was undertaken using a wide range of storage conditions. Special attention must be paid to sample handling to avoid light degradation of the compounds.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16002351&dopt=Abstract

Characterization of the discriminable stimulus produced by 2-BFI: effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine and ibogaine.

Characterization of the discriminable stimulus produced by 2-BFI: effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine and ibogaine. 1. The molecular nature and functions of the I(2) subtype of imidazoline binding sites are unknown but evidence suggests an association with monoamine oxidase (MAO). Rats can distinguish the selective imidazoline I(2)-site ligand 2-BFI from vehicle in drug discrimination, indicating functional consequences of occupation of these sites. We have used drug discrimination to investigate the nature of the discriminable stimulus, especially in relation to MAO inhibition. 2. Following training to distinguish 2-BFI 7 mg kg(-1) i.p. from saline vehicle in two-lever operant-chambers, male Hooded Lister rats underwent sessions where test substances were given instead and the proportion of lever presses on the 2-BFI-associated lever (substitution) recorded. 3. 2-BFI; its cogeners BU216, BU224, BU226 and LSL60101; the reversible MAO-A inhibitors moclobemide and RO41-1049; the beta-carbolines harmane, norharmane and harmaline which also reversibly inhibit MAO-A, and the anti-addictive substance ibogaine exhibited potent, dose-dependent substitution for 2-BFI. 4. Agmatine, and LSL60125 substituted at one dose only. The reversible MAO-B inhibitors lazabemide and RO16-1649; the sigma(2)-site ligand SKF10,047 and the I(2A)-site ligand, amiloride, failed to substitute. The irreversible inhibitor of MAO, deprenyl, substituted for 2-BFI while clorgyline did not. 5. These results suggest imidazoline I(2) site ligands produce a common discriminable stimulus that appears associated with reversible inhibition of MAO-A rather than MAO-B, possibly through increases in extracellular concentration of one or more monoamines. Ibogaine exhibits a commonality in its subjective effects with those of I(2)-site ligands.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11877331&dopt=Abstract

Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus.

The experiments strongly suggested that the reason why Purkinje cells die so easily after global brain ischemia relates to deficiencies in aldolase C and EAAT4 that allow them to survive pathologically intense synaptic input from the inferior olive after the restoration of blood flow. This conclusion is based on: (a) the remarkably tight correspondence between the regional absence of aldolase C and EAAT4 in Purkinje cells and the patterned loss of Purkinje cells after a bout of global brain ischemia; (b) the necessity of the olivocerebellar pathway for the ischemic death of Purkinje cells; and (c) the build-up of pathologically synchronous and high-frequency burst activity within the inferior olive during recovery from ischemia. Indeed, the correspondence between the absence of aldolase C and EAAT4 to sensitivity to ischemia could be demonstrated for zones of Purkinje cells as small as two neurons. A second finding was that Purkinje cells are not uniformly sensitive to transient ischemia, since they die most frequently in zones where aldolase C and EAAT4 are absent. One implication of the experiment is that factors beyond the unique synaptic and membrane properties of Purkinje cells play an important role in determining this neuron’s high sensitivity to ischemia. The data strongly imply that two properties of Purkinje cells that make them susceptible to ischemic death are their reduced capability to sequester glutamate and reduced ability to generate energy during anoxia. The patterned death of Purkinje cells is sufficient to induce a form of audiogenic myoclonus, as determined with a neurotoxic dose of ibogaine. Ibogaine-induced myoclonus is recognized behaviorally as a reduced ability to habituate to a startle stimulus and resembles the myoclonic jerk of rats during recovery from a prolonged bout of global brain ischemia. Commonalities of ischemia and ibogaine-induced neurodegeneration are the intricately striped Purkinje cell loss in the posterior lobe and a nearly complete deafferentation of the lateral aspect of the fastigial nucleus from the cerebellar cortex, in particular the dorsolateral protuberance. Thus, the data point strongly to a cerebellar contribution to audiogenic myoclonus. Single-neuron electrophysiology experiments in monkeys have demonstrated that the evoked activity in the deep cerebellar nuclei occurs too late to initiate the startle response (60) and electromyography of the postischemic myoclonus of rats corroborates this view (see Chapter 31) (20). However, the nearly complete loss of GABAergic terminals in the dorsolateral protuberance after Purkinje cell death would be expected to dramatically increase its tonic firing and the background excitation of the brain-stem structures that it innervates. The fastigial nucleus innervates a large number of autonomic and motor structures in the brainstem and diencephalon, including the ventrolateral nucleus of the thalamus and the gigantocellular reticular nucleus in the medulla–structures that have been implicated in human posthypoxic myoclonus (6, 7). We propose that the posthypoxic myoclonic jerk of rats is, at least in part, due to disinhibition of the fastigial nucleus produced by patterned Purkinje cell death in the vermis. The argument is as follows: the loss of GABAergic inhibition in the fastigial nucleus after ischemia leads to diaschisis of the motor thalamus and reticular formation which, in turn, is responsible for enhanced motor excitability and myoclonus. That the audiogenic myoclonus after global brain ischemia in the rat gradually resolves over a period of 2 to 3 weeks is consistent with this view, as restoration of background excitability after CNS damage in rats has been documented to occur within this time-frame (61). Our view brings together the physiologic finding that posthypoxic myoclonus appears to originate in the sensory-motor cortices and/or reticular formation with the consistent anatomical finding of Purkinje cell loss after ischemia, and explains the puzzle of Marsden’s unique cases of myoclonus associated with coeliac disease (1). Moreover, our argument is consistent with findings both in rats (62, 63) and humans (64) that damage to the vermis impairs the long-term habituation of the startle reflex. It remains to be determined whether the pathologically enhanced startle responses after vermal damage resemble brain-stem reticular or cortical myoclonus at the electrophysiologic level of analysis. What is the purpose of the regional expression of aldolase C and EAAT4 in Purkinje cells? The close correspondence between the spatial distribution of aldolase C and the parasagittal anatomy of the cerebellum (48) has led to the view that aldolase C may help specify connectivity during development. While the present experiments do not address this issue, they underscore the fact that aldolase plays a fundamental role in metabolism. Because Purkinje cells have a repressed expression of aldolase A (31), whatever role the absence of aldolase C may play during development comes at the price of metabolic frailty later in adulthood. From another point of view, aldolase C and EAAT4 appear to confer upon Purkinje cells the ability to survive their own climbing fiber. Indeed, climbing fibers form a distributed synapse that synchronously releases glutamate (or aspartate) at all levels of the dendritic tree simultaneously (65, 66). Such synchronous activation triggers calcium influx throughout the Purkinje cell dendrites at a magnitude that is unparalleled in the nervous system (12), and, thus, places an extraordinarily high metabolic demand on the Purkinje cell. The apparently reduced level of aldolase in a subpopulation of Purkinje cells provides the condition for energy failure and death during anoxia so long as the climbing fibers are intact or when climbing fiber activation is pharmacologically enhanced under normoxic conditions, such as after ibogaine (53-56). Lastly, the argument that diaschisis produced by patterned cerebellar degeneration leads to thalamo-cortical and reticular hyperexcitability agrees with C. David Marsden and his colleagues’ bold demonstration of an inhibitory influence of cerebellar cortex on motor cortex in humans (67). Our anatomic data indicate that the spatially distinct zones of Purkinje cells, which are killed by global brain ischemia, may be the origin of such inhibition.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11968459&dopt=Abstract

Ibogaine analogues. Synthesis and preliminary pharmacological evaluation of 7-heteroaryl-2-azabicyclo[2.2.2]oct-7-enes.

Ibogaine analogues. Synthesis and preliminary pharmacological evaluation of 7-heteroaryl-2-azabicyclo[2.2.2]oct-7-enes. Synthesis of 7-heteroaryl-2-azabicyclo[2.2.2]oct-7-enes by cycloaddition and subsequent cross-coupling reaction is described. Binding affinity of these novel compounds towards the characteristic receptorial targets of ibogaine is illustrated.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12614886&dopt=Abstract

Extraction studies of Tabernanthe iboga and Voacanga africana.

The root bark of Tabernanthe iboga contains ibogaine as its predominant alkaloid and has been an important source of it. Ibogaine is used experimentally to interrupt drug addiction and allow therapeutic intervention, but is currently unaffordable to doctors in less economically developed countries. To meet this need, an extraction of alkaloids from T. iboga root bark was optimized and simplified to use only diluted vinegar and ammonia, and was successfully applied to related alkaloids from Voacanga africana bark also. The alkaloids were converted to their hydrochlorides and purified, and the minor alkaloids were recovered.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11942686&dopt=Abstract

Nature-inspired indolyl-2-azabicyclo[2.2.2]oct-7-ene derivatives as promising agents for the attenuation of withdrawal symptoms: synthesis of 20-desethyl-20-hydroxymethyl-11-demethoxyibogaine.

Microwave assisted Diels-Alder cycloaddition of 5-Br-N-benzylpyridinone (2) with methyl acrylate is described to gain an easy access to 7-bromo-2-benzyl-3-oxo-2-aza-5 or 6-carbomethoxy bicyclo[2.2.2]oct-7-enes (3)-(6). The preparation of the ibogaine analogue 20-desethyl-(20-endo)-hydroxymethyl-11-demethoxyibogaine (17) is described by stereoselective hydrogenation of the C(7)-C(8) double bond. Biological evaluation showed an interesting in vitro binding profile toward dopamine transporter, serotonin transporter and opioid receptor systems accompanied by an antiwithdrawal effect in mice for hydroxymethyl 7-indolyl-2-aza-bicyclo[2.2.2]oct-2-ene (14). The simplification of the ibogaine structure appears as a promising approach toward the design of compounds that could reduce the withdrawal symptoms.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16753910&dopt=Abstract

Client and counselor attitudes toward the use of medications for treatment of opioid dependence.

Attitudes, perceived social norms, and intentions were assessed for 376 counselors and 1,083 clients from outpatient, methadone, and residential drug treatment programs regarding four medications used to treat opiate dependence: methadone, buprenorphine, clonidine, and ibogaine. Attitudes, social norms, and intentions to use varied by treatment modality. Methadone clients and counselors had more positive attitudes toward the use of methadone, whereas their counterparts in residential and outpatient settings had neutral or negative assessments. Across modalities, attitudes, perceived social norms, and intentions toward the use of buprenorphine were relatively neutral. Assessments of clonidine and ibogaine were negative for clients and counselors in all settings. Social normative influences were dominant across settings and medications in determining counselor and client intentions to use medications, suggesting that perceptions about beliefs of peers may play a critical role in use of medications to treat opiate dependence.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=17306729&dopt=Abstract

A review of chemical agents in the pharmacotherapy of addiction.

Chemical substance abuse has tormented mankind throughout history. A number of chemical approaches have been employed in an attempt to treat chemical addiction. Unfortunately, most of these have proven unsuccessful though several chemical entities have been shown to be moderately effective. The naturally occurring alkaloid ibogaine has been reported to interrupt the cravings for alcohol, cocaine and opiates. Other alkaloids from Tabernanthe iboga, such as ibogamine and tabernanthine, provide insight into the structure activity relationship at the different receptors believed to be involved in addiction. The synthetic iboga alkaloid congener, 18-MC, also shows potential as an anti-addictive agent without the hallucinogenic effects of ibogaine. Additionally, acamprosate, BP 897, GBR12909, lofexidine and memantine have shown promising results in the treatment of addiction. All of these leads provide a start for the medicinal chemist to design anti-addictive agents, since currently no drugs are approved in the U.S. for the treatment of addictions to cocaine, methamphetamine, other stimulants or PCP.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12369879&dopt=Abstract

Noribogaine (12-hydroxyibogamine): a biologically active metabolite of the antiaddictive drug ibogaine.

Noribogaine (12-hydroxyibogamine): a biologically active metabolite of the antiaddictive drug ibogaine. Ibogaine (IBO) is a plant-derived alkaloid that is being evaluated as a possible medication for substance use disorders. When administered peripherally to monkeys and humans, IBO is rapidly converted to an o-demethylated metabolite, 12-hydroxyibogamine (NORIBO). We have found in rats that peak blood levels of NORIBO can exceed those of the parent compound, and NORIBO persists in the bloodstream for at least 24 h. Surprisingly few studies have examined the in vivo biological activity of NORIBO. In the present series of experiments, we compared the effects of intravenous (i.v.) administration of IBO and NORIBO (1 and 10 mg/kg) on unconditioned behaviors, circulating stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. IBO caused dose-related increases in tremors and forepaw treading, whereas NORIBO did not. Both IBO and NORIBO produced significant elevations in plasma corticosterone and prolactin, but IBO was more potent as a stimulator of corticosterone secretion. Neither drug affected extracellular DA levels in the nucleus accumbens. However, both IBO and NORIBO increased extracellular 5-HT levels, and NORIBO was more potent in this regard. The present data demonstrate that NORIBO is biologically active and undoubtedly contributes to the in vivo pharmacological profile of IBO in rats. Most importantly, NORIBO appears less likely to produce the adverse effects associated with IBO (i.e., tremors and stress-axis activation), suggesting that the metabolite may be a safer alternative for medication development.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11085335&dopt=Abstract

Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-D-aspartate receptors.

Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-D-aspartate receptors. Ibogaine (IBO) is an alkaloid with putative antiaddictive properties, alleviating opiates dependence and withdrawal. The glutamate N-methyl-D-aspartate (NMDA) receptors have been implicated in the physiological basis of drug addiction; accordingly, IBO acts as a noncompetitive NMDA antagonist. The purpose of this study was to evaluate the effects of IBO on naloxone-induced withdrawal syndrome in morphine-dependent mice, focusing on the role of NMDA receptors. Jumping, a major behavioral expression of such withdrawal, was significantly (P<.01) inhibited by IBO (40 and 80 mg/kg, 64.2% and 96.9% inhibition, respectively) and MK-801 (0.15 and 0.30 mg/kg, 67.3% and 97.7%, respectively) given prior to naloxone. Coadministration of the lower doses of IBO (40 mg/kg) and MK-801 (0.15 mg/kg) results in 94.7% inhibition of jumping, comparable to the effects of higher doses of either IBO or MK-801. IBO and MK-801 also significantly inhibited NMDA-induced (99.0% and 71.0%, respectively) jumping when given 30 min (but not 24 h) prior to NMDA in nonaddictive mice. There were no significant differences in [3H]MK-801 binding to cortical membranes from naive animals, morphine-dependent animals, or morphine-dependent animals treated with IBO or MK-801. This study provides further evidence that IBO does have an inhibitory effect on opiate withdrawal symptoms and suggests that the complex process resulting in morphine withdrawal includes an IBO-sensitive functional and transitory alteration of NMDA receptor.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12921910&dopt=Abstract

A dose-response study of ibogaine-induced neuropathology in the rat cerebellum.

A dose-response study of ibogaine-induced neuropathology in the rat cerebellum. Ibogaine (IBO) is an indole alkaloid from the West African shrub, Tabernanthe iboga. It is structurally related to harmaline, and both these compounds are rigid analogs of melatonin. IBO has both psychoactive and stimulant properties. In single-blind trials with humans, it ameliorated withdrawal symptoms and interrupted the addiction process. However, IBO also produced neurodegeneration of Purkinje cells and gliosis of Bergmann astrocytes in the cerebella of rats given even a single dose (100 mg/kg, ip). Here, we treated rats (n = 6 per group) with either a single ip injection of saline or with 25 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg of IBO. As biomarkers of cerebellar neurotoxicity, we specifically labeled degenerating neurons and axons with silver, astrocytes with antisera to glial fibrillary acidic protein (GFAP), and Purkinje neurons with antisera to calbindin. All rats of the 100-mg/kg group showed the same pattern of cerebellar damage previously described: multiple bands of degenerating Purkinje neurons. All rats of the 75-mg/ kg group had neurodegeneration similar to the 100-mg/kg group, but the bands appeared to be narrower. Only 2 of 6 rats that received 50 mg/kg were affected; despite few degenerating neuronal perikarya, cerebella from these rats did contain patches of astrocytosis similar to those observed with 75 or 100 mg/kg IBO. These observations affirm the usefulness of GFAP immunohistochemistry as a sensitive biomarker of neurotoxicity. None of the sections from the 25-mg/kg rats, however stained, were distinguishable from saline controls, indicating that this dose level may be considered as a no-observable-adverse-effect level (NOAEL).

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=10966515&dopt=Abstract

Metabolism of 18-methoxycoronaridine, an ibogaine analog, to 18-hydroxycoronaridine by genetically variable CYP2C19.

Metabolism of 18-methoxycoronaridine, an ibogaine analog, to 18-hydroxycoronaridine by genetically variable CYP2C19. 18-Methoxycoronaridine, a newly developed ibogaine analog, has been reported to decrease the self-administration of morphine, cocaine, ethanol, and nicotine. It has also been reported to attenuate naltrexone-precipitated signs of morphine withdrawal. In this study, three metabolites of 18-methoxycoronaridine (18-MC) were separated and identified by high-performance liquid chromatography-electrospray ionization-mass spectrometry-mass spectrometry (HPLC-ESI-MS-MS); the major metabolite was 18-hydroxycoronaridine (18-HC). The other two metabolites were elucidated as hydroxylated metabolites on the basis of their MS-MS spectra. Catalytic studies of 18-MC O-demethylase activity in human liver microsomes indicate that one high affinity enzyme is involved in this reaction (K(m) from 2.81 to 7.9 microM; V(max) from 0.045 to 0.29 nmol/mg/min). In cDNA-expressing microsomes, only CYP2C19 displayed significant 18-MC O-demethylase activity (K(m) 1.34 microM; V(max) 0.21 nmol/mg/min). S-Mephenytoin, a selective CYP2C19 inhibitor, inhibited 18-MC O-demethylation by 65% at a concentration of 2 times its K(I), and antibodies against rat 2C (human CYP2C8, 2C9, 2C19) inhibited 18-HC formation by 70%. Studies with other cytochrome P450 (P450)-selective chemical inhibitors and antibodies failed to demonstrate an appreciable role for other P450s in this reaction. In addition, in microsomes from five different human livers, 18-MC O-demethylation correlated with S-mephenytoin 4’hydroxylase activity but not with other P450 probe reactions. These data indicate that 18-HC formation is the predominant pathway of 18-MC metabolism in vitro in human liver microsomes and that this metabolic pathway is primarily catalyzed by the polymorphic CYP2C19. The apparent selectivity of this pathway for CYP2C19 suggests 18-MC as a potentially useful probe of CYP2C19 activity in vitro and in vivo.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12019193&dopt=Abstract

Sigma-1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia.

Sigma receptors are putative targets for neuroprotection following ischemia; however, little is known on their mechanism of action. One of the key components in the demise of neurons following ischemic injury is the disruption of intracellular calcium homeostasis. Fluorometric calcium imaging was used to examine the effects of sigma receptor activation on changes in intracellular calcium concentrations ([Ca(2+)](i)) evoked by in vitro ischemia in cultured cortical neurons from embryonic rats. The sigma receptor agonist, 1,3-di-o-tolyl-guanidine (DTG), was shown to depress [Ca(2+)](i) elevations observed in response to ischemia induced by sodium azide and glucose deprivation. Two sigma receptor antagonists, metaphit [1-(1-(3-isothiocyanatophenyl)-cyclohexyl)-piperidine] and BD-1047 (N-[2-3,4-dichlorophenyl)-ethyl]-N-methyl-2-(dimethylamino)ethylamine), were shown to blunt the ability of DTG to inhibit ischemia-evoked increases in [Ca(2+)](i), revealing that the effects are mediated by activation of sigma receptors and not via the actions of DTG on nonspecific targets such as N-methyl-d-aspartate receptors. DTG inhibition of ischemia-induced increases in [Ca(2+)](i) was mimicked by the sigma-1 receptor-selective agonists, carbetapentane, (+)-pentazocine and PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], but not by the sigma-2-selective agonist, ibogaine, showing that activation of sigma-1 receptors is responsible for the effects. In contrast, DTG, carbetapentane, and ibogaine blocked spontaneous, synchronous calcium transients observed in our preparation at concentrations consistent with sigma receptor-mediated effects, indicating that both sigma-1 and sigma-2 receptors regulate events that affect [Ca(2+)](i) in cortical neurons. Our studies show that activation of sigma receptors can ameliorate [Ca(2+)](i) dysregulation associated with ischemia in cortical neurons and, thus, identify one of the mechanisms by which these receptors may exert their neuroprotective properties.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16988055&dopt=Abstract

Application of electrophysiological method to study interactions between ibogaine and cocaine.

Application of electrophysiological method to study interactions between ibogaine and cocaine. The psychoactive indole alkaloid, ibogaine (IBO), has been investigated for over a decade concerning its reported anti-addictive properties for opioids as well as psychomotor stimulants. The mechanism for the anti-addictive action of IBO is still unclear. IBO interactions with opioid, NMDA, nicotinic, adrenergic, and serotonergic receptor sites have been suggested. The involvement of the dopaminergic system in IBO action is well documented. Increased or decreased levels of dopamine (DA) in specific brain regions following IBO pretreatment have been seen concomitantly with increased or decreased motor activity after subsequent amphetamine or cocaine administration. In this report, in vivo electrophysiological measures were monitored in awake adult male rats in order to investigate alterations of the electrocorticogram (ECoG) resulting from interactions between IBO and cocaine (COC). Rats were implanted bilaterally with bipolar ECoG electrodes. They were either injected with saline, COC alone (20 mg/kg, i.p.) or IBO (50 mg/kg, i.p.) and COC 1 hr later. The concentrations of DA, 5-HT, and their metabolites DOPAC, HVA, and 5-HIAA were assessed in the caudate nucleus in separate groups of saline-, COC-, and IBO/COC-treated rats. An alpha1 power increase was observed within 10 min after COC injection, which lasted for less than 20 min. A desynchronization over alpha2 and both beta power bands was observed throughout the recording. In IBO/COC-treated rats, a significant increase in delta, theta, and alpha1 power occurred within 20 min after COC injection (p <0.05). This effect lasted for up to an hour. DA levels significantly increased after COC only and decreased after IBO administration. A further decrease in levels of DA was observed in IBO/COC-treated rats. DA turnover increased significantly after IBO alone but was not observed after IBO/COC treatment. The alterations in ECoG and neurotransmitter levels suggest a decreased response to COC following IBO pretreatment.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11085337&dopt=Abstract

Ibogaine may help drug addicts live the ‘never again’.

Ibogaine may help drug addicts live the ‘never again’.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16909175&dopt=Abstract

From the roots up: ibogaine and addict self-help.

From the roots up: ibogaine and addict self-help.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705113&dopt=Abstract

Ibogaine: proceedings of the First International Conference.

Ibogaine: proceedings of the First International Conference.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705119&dopt=Abstract

Addiction research. Ibogaine therapy: a ‘vast, uncontrolled experiment’.

Addiction research. Ibogaine therapy: a ‘vast, uncontrolled experiment’.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15831735&dopt=Abstract

Characterization of multiple sites of action of ibogaine.

Characterization of multiple sites of action of ibogaine.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705104&dopt=Abstract

Anxiogenic action of ibogaine.

Anxiogenic action of ibogaine.

http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705110&dopt=Abstract
Ibogaine as a glutamate antagonist: relevance to its putative antiaddictive properties.
Ibogaine as a glutamate antagonist: relevance to its putative antiaddictive properties.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705116&dopt=Abstract
Case studies of ibogaine treatment: implications for patient management strategies.
Case studies of ibogaine treatment: implications for patient management strategies.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705114&dopt=Abstract
Modulation of the effects of rewarding drugs by ibogaine.
Modulation of the effects of rewarding drugs by ibogaine.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705109&dopt=Abstract
Ibogaine neurotoxicity assessment: electrophysiological, neurochemical, and neurohistological methods.
Ibogaine neurotoxicity assessment: electrophysiological, neurochemical, and neurohistological methods.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705108&dopt=Abstract
Changes in gene expression and signal transduction following ibogaine treatment.
Changes in gene expression and signal transduction following ibogaine treatment.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705105&dopt=Abstract
A contemporary history of ibogaine in the United States and Europe.
A contemporary history of ibogaine in the United States and Europe.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705112&dopt=Abstract
Ibogaine in acute opioid withdrawal. An open label case series.
Ibogaine in acute opioid withdrawal. An open label case series.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=10911935&dopt=Abstract
Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener.
Mechanisms of action of ibogaine: relevance to putative therapeutic effects and development of a safer iboga alkaloid congener.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705115&dopt=Abstract
Ibogaine in the treatment of heroin withdrawal.
Ibogaine in the treatment of heroin withdrawal.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705106&dopt=Abstract
Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine.
Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705118&dopt=Abstract
Indole alkaloids from Tabernaemontana australis (Muell. Arg) Miers that inhibit acetylcholinesterase enzyme.
Ten indole alkaloids from the chloroform extract of stalk of Tabernaemontana australis (Muell. Arg) Miers were tentatively identified by GC-MS, viz., coronaridine (1), voacangine (2), voacangine hydroxyindolenine (3), rupicoline (4), ibogamine (5), ibogaine (6), ibogaline (7), desethyl-voacangine (8), voachalotine (9), and affinisine (10). Of these, the first four were isolated by silica gel open column chromatography, identified by uni- and bidimensional NMR, IR, MS and showed anti-cholinesterasic activity at the same concentration as the reference compounds physostigmine and galanthamine (detection limit of 0.01mM) by TLC assay using the modified Ellman’s method.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15911323&dopt=Abstract
Nicotinic agonists, antagonists, and modulators from natural sources.
1. Acetylcholine receptors were initially defined as nicotinic or muscarinic, based on selective activation by two natural products, nicotine and muscarine. Several further nicotinic agonists have been discovered from natural sources, including cytisine, anatoxin, ferruginine, anabaseine, epibatidine, and epiquinamide. These have provided lead structures for the design of a wide range of synthetic agents. 2. Natural sources have also provided competitive nicotinic antagonists, such as the Erythrina alkaloids, the tubocurarines, and methyllycaconitine. Noncompetitive antagonists, such as the histrionicotoxins, various izidines, decahydroquinolines, spiropyrrolizidine oximes, pseudophrynamines, ibogaine, strychnine, cocaine, and sparteine have come from natural sources. Finally, galanthamine, codeine, and ivermectin represent positive modulators of nicotinic function, derived from natural sources. 3. Clearly, research on acetylcholine receptors and functions has been dependent on key natural products and the synthetic agents that they inspired.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16075378&dopt=Abstract
The adverse effects of hallucinogens from intramural perspective.
Very recently, after a long-lasting, worldwide moratorium on research of hallucinogenic agents, a good number of advanced countries have been revising their position, and start to approve testing the physiological and therapeutic effects of hallucinogens in human subjects. The purpose of this article is to review safety information available in the literature on hallucinogen use, and sort out those data from the reported complications of their abuse. Because of prohibitory regulations of the last 35 years, there are difficulties in achieving this kind of evaluation. Our approach has to be broad, and at times retrospective, in contrast to the well-controlled, focused, prospective design of the premarketing trials of legal drugs. The article summarizes the analyses in anticipation of supportive regulatory changes for the use of hallucinogens in well controlled studies and strictly supervised clinical trials. Keywords: adverse effects, ayahuasca, N,N-dimethyltryptamine, hallucinogenic agents, ibogaine, lysergic acid diethylamide, N-methyl-3,4-methylenedioxyamphetamine, psilocybin, therapeutic use.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=17211054&dopt=Abstract
Hallucinogens and redemption.
This article examines drug substitution with regard to hallucinogens (ayahuasca, ibogaine, peyote and LSD) set within the concept of redemption. The model examines both religious and secular approaches to the contemporary use of hallucinogens in drug substitution, both by scientists and in religious settings worldwide. The redemptive model posits that the proper use of one psychoactive substance within a spiritual or clinical context helps to free an individual from the adverse effects of their addiction to another substance and thus restores them as functioning members of their community or group. Data is drawn from the U.S., Brazil, Peru, and West Africa. Two principle mechanisms for this are proposed: the psychological mechanism of suggestibility is examined in terms of the individual reaching abstinence goals from addictive substances such as alcohol and opiates. Neurophysiological and neurochemical mechanisms to understand the efficacy of such substitution are highlighted from ongoing research on hallucinogens. Research by two of the authors with the Unaio do Vegetal (UDV) Church in Brazil is examined in terms of the model.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12422934&dopt=Abstract
Complementary medicines in psychiatry: review of effectiveness and safety.
BACKGROUND: The use of complementary medicines in those with mental health problems is well documented. However, their effectiveness is often not established and they may be less harmless than commonly assumed. AIMS: To review the complementary medicines routinely encountered in psychiatric practice, their effectiveness, potential adverse effects and interactions. METHOD: Electronic and manual literature search on the effectiveness and safety of psychotropic complementary medicines. RESULTS: Potentially useful substances include ginkgo and hydergine as cognitive enhancers, passion flower and valerian as sedatives, St John’s wort and s-adenosylmethionine as antidepressants, and selenium and folate to complement antidepressants. The evidence is less conclusive for the use of omega-3 fatty acids as augmentation treatment in schizophrenia, melatonin for tardive dyskinesia and 18-methoxycoronaridine, an ibogaine derivative, for the treatment of cocaine and heroin addiction. CONCLUSIONS: Systematic clinical trials are needed to test promising substances. Meanwhile, those wishing to take psychotropic complementary medicines require appropriate advice.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16449696&dopt=Abstract
Synthesis of isoquinuclidine analogs of chloroquine: antimalarial and antileishmanial activity.
The isoquinuclidine (2-azabicyclo[2.2.2]octane) ring system may be viewed as a semi-rigid boat form of the piperidine ring and, when properly substituted, a scaffold for rigid analogs of biologically active ethanolamines and propanolamines. It is present in natural products (such as ibogaine and dioscorine) that display interesting pharmacological properties. In this study, we have expanded our continuing efforts to incorporate this ring system in numerous pharmacophores, by designing and synthesizing semirigid analogs of the antimalarial drug chloroquine. The analogs were tested in vitro against Plasmodium falciparum strains and Leishmania donovani promastigote cultures. Compounds 6 and 13 displayed potent antimalarial activity against both chloroquine-susceptible D6 and the -resistant W2 strains of P. falciparum. All analogs also demonstrated significant antileishmanial activity with compounds 6 and 13 again being the most potent. The fact that these compounds are active against both chloroquine-resistant and chloroquine-sensitive strains as well as leishmanial cells makes them promising candidates for drug development.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=17400457&dopt=Abstract
Evaluation of neurodegeneration in scrapie-infected animals by selective methods that detect cellular degeneration.
Scrapie is a fatal neurodegenerative disease of sheep and goats. The precise details of neuronal and neurite degeneration in scrapie-infected animals remain unknown. Using specific silver staining methods, we compared the neurodegeneration caused by treatment of rats with kainic acid (KA) or ibogaine (IBO) to the neuropathology observed in mice infected with the C602 strain of scrapie. As reported previously, KA resulted in extensive silver labeling of neurons, especially in the cortex, putamen and hippocampus. IBO silver labeling was observed only in small clusters of Purkinje neurons in the paravermal region of the cerebellum. However, in scrapie-infected mice, a few silver stained neurons (differing from the dark degenerating neurons observed following neurotoxic exposure) were found in layer II of cortex, cingulate cortex, zona incerta, thalamus and hypothalamus. Some silver grains were observed in glial-like cells, especially those in the paraventricular region. Degenerating axons were positive for silver staining and were found in the cortex, cingulate cortex, corpus callosum, habenulae, septum, fornix, thalamus, caudate putamen and a few in fasciculus retroflexus and substantia nigra. Our results suggest that the limbic system is one of the important loci for the neurodegenerative effect of at least some scrapie strains.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11489267&dopt=Abstract
Gateways to clinical trials.
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com/. This issue focuses on the following selection of drugs: Adalimumab, adenosine triphosphate, alemtuzumab, alendronate sodium/cholecalciferol, aliskiren fumarate, AMGN-0007, aminolevulinic acid methyl ester, anakinra, anidulafungin, aripiprazole, atomoxetine hydrochloride; Bevacizumab, bosentan; Calcipotriol/beta methasone dipropionate, caldaret hydrate, caspofungin acetate, cetuximab, cinacalcet hydrochloride, clopidogrel, cocaine-BSA conjugate, conivaptan hydrochloride, Cypher; Darbepoetin alfa, delmitide, desloratadine, desmoteplase, desoxyepothilone B, disufenton sodium, DU-176b, duloxetine hydrochloride, dutasteride; EBV-specific CTLs, ecogramostim, edodekin alfa, efalizumab, eletriptan, emtricitabine, entecavir, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, etoricoxib, everolimus, ezetimibe; Fanapanel, fondaparinux sodium; Gefitinib, GTI-2040, GW-501516; Her2 E75-peptide vaccine, human insulin; Ibogaine, icatibant acetate, Id-KLH vaccine, imatinib mesylate, immune globulin subcutaneous [human], indacaterol, inolimomab, ipilimumab, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, lanthanum carbonate, lenalidomide, levocetirizine, levodopa methyl ester hydrochloride/carbidopa, levodopa/carbidopa/entacapone, lidocaine/prilocaine; Maraviroc, mecasermin, melevodopa hydrochloride, mepolizumab, mitumomab; Nesiritide; Omalizumab, oral insulin; Parathyroid hormone (human recombinant), patupilone, pegaptanib sodium, PEG-filgrastim, pemetrexed disodium, photochlor, pimecrolimus, posaconazole, prasterone, prasugrel, pregabalin, prilocaine, PRX-00023; QS-21; Ranibizumab, ranirestat, rhodamine 123, rotigaptide; Sarcosine, sirolimus-eluting stent, sitaxsentan sodium, solifenacin succinate, Staphylococcus aureus vaccine; Tadalafil, talactoferrin alfa, talaporfin sodium, Taxus, tecadenoson, tegaserod maleate, telithromycin, temsirolimus, tenofovir disoproxil fumarate, teriparatide, terutroban sodium, tesaglitazar, tesmilifene hydrochloride, TG-100115, tigecycline, torcetrapib; Ularitide; Valproic acid, sodium, voriconazole; Zotarolimus, zotarolimus-eluting stent.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16801985&dopt=Abstract
Iboga compounds reverse the behavioural disinhibiting and corticosterone effects of acute methamphetamine: Implications for their antiaddictive properties.
This study investigated the effects of pretreatment with the putative antiaddictive compound, ibogaine (IBO), and its synthetic derivative, 18-methoxycoronaridine (18-MC), on the changes in behaviour in an elevated plus maze and the changes in corticosterone (CORT) produced by a low dose of methamphetamine (METH). In the elevated plus maze, the acute administration of METH (0.1 mg/kg ip, -20 min) produced an increase in both the number and the duration of open arm entries relative to saline (SAL)-treated controls. No effect of METH administration was observed on the total number of arm entries. These data indicated that METH alone produced either anxiolysis or behavioural disinhibition in this paradigm. More consistent with the latter possibility, the open arm behaviour of METH controls was associated with an increase in plasma levels of CORT, supporting a facilitatory role for CORT in this METH-induced effect. Pretreatment with both IBO and 18-MC (40 mg/kg ip, 19 h earlier) antagonized the behavioural disinhibiting effects of acute METH without altering locomotor activity. In addition, both iboga agents antagonized the increase in CORT produced by METH. These data provide insight into yet another potential mechanism through which iboga compounds may exert their antiaddictive effects, a reversal of the behavioural disinhibiting properties of stimulant drugs. Furthermore, these data indicate that this reversal is related to effects of iboga compounds on the stimulation of neuroendocrine systems by stimulant drugs.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11509208&dopt=Abstract
Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats.
RATIONALE: The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative antiaddictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. OBJECTIVES: As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. METHODS: The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. RESULTS: Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. CONCLUSIONS: Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=10972470&dopt=Abstract
Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine.
18-Methoxyroconaridine (18-MC), a synthetic derivative of ibogaine, reduces morphine self-administration and alleviates several signs of acute opioid withdrawal in rats. Although there is already well documented evidence of the mechanism mediating 18-MC’s action to reduce the rewarding effects of morphine, nothing is known about the mechanism responsible for 18-MC’s attenuation of opioid withdrawal. In vitro studies have demonstrated that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors (IC50=0.75 microM), which are predominantly located in the medial habenula and interpeduncular nuclei. Previous work indicating that alpha3beta4 nicotinic receptors mediate 18-MC’s effects on drug self-administration prompted us to assess whether brain areas having high or moderate densities of alpha3beta4 receptors might be involved in 18-MC’s modulation of opioid withdrawal. To test this possibility, 18-MC was locally administered into the medial habenula, interpeduncular nucleus and locus coeruleus of morphine-dependent rats; this treatment was followed by naltrexone to precipitate a withdrawal syndrome. Pretreatment with various doses of 18-MC into the locus coeruleus significantly reduced wet-dog shakes, teeth chattering, burying and diarrhea, while pretreatment into the medial habenula attenuated teeth chattering, burying, and weight loss. Some doses of 18-MC administered into the interpeduncular nucleus significantly ameliorated rearing, teeth chattering, and burying, while other doses exacerbated diarrhea and teeth chattering. The present findings suggest that 18-MC may act in all three nuclei to suppress various signs of opioid withdrawal.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16289028&dopt=Abstract
Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.
RATIONALE: Phencyclidine (PCP) binds with high affinity to a site located within the ionophore of N-methyl- D-aspartate (NMDA) receptors. Previous studies have demonstrated that PCP and other high-affinity NMDA channel blockers reliably disrupt prepulse inhibition (PPI) of acoustic startle, an animal model of sensorimotor gating used to study attentional deficits associated with schizophrenia. Recently, a number of low-affinity NMDA channel blockers that exhibit minimal PCP-like effects in humans at therapeutic doses have been developed. OBJECTIVES: The purpose of this study was to evaluate the effects on PPI of NMDA channel blockers with varying affinities for the channel site as well as different specificities for NMDA receptors. METHODS: Sprague-Dawley rats were presented with multiple stimulus presentation trials, including pulse-alone and PPI trials. RESULTS: As expected, the high-affinity ligands dizocilpine and dextrorphan disrupted PPI at doses that did not affect the response during pulse-alone trials. Low-affinity drugs produced a mixed pattern of results. Whereas dextromethorphan and memantine disrupted PPI, orphenadrine, amantadine, desipramine, and alaproclate did not affect this response. Ibogaine also disrupted PPI, but only within a dose range that severely decreased the startle response during pulse-alone trials. CONCLUSIONS: These results suggest that not all NMDA channel blockers share PCP’s effect of PPI disruption. In addition, they suggest caution in the use of supratherapeutic doses of these compounds and in their use in vulnerable populations (e.g., schizophrenic patients).
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12459931&dopt=Abstract
sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons.
The sigma receptors have been implicated in the regulation of the cardiovascular system, and sigma-1 receptor transcripts have been found in parasympathetic intracardiac neurons. However, the cellular function of sigma-1 receptors in these cells remains to be determined. Effects of sigma receptor activation on voltage-activated K(+) channels and action potential firing were studied in isolated intracardiac neurons using whole-cell patch-clamp recording techniques. Activation of sigma receptors reversibly blocked delayed outwardly rectifying potassium channels, large conductance Ca(2+)-sensitive K(+) channels, and the M-current with maximal inhibition >80%. The inhibition of K(+) channels by sigma ligands was dose-dependent, and the rank order potency of (+)-pentazocine > ibogaine > 1,3-di-O-tolyguanidin (DTG) suggests that the effect is mediated by sigma-1 receptor activation. Preincubation of neurons with the irreversible sigma receptor antagonist metaphit blocked DTG-induced inhibition of K(+) channels, confirming that the effect is mediated by sigma receptor activation. Although bath application of sigma ligands depolarized intracardiac neurons, the number of action potentials fired by the cells in response to depolarizing current pulses was decreased in the presence of these drugs. Neither dialysis of the neurons nor application of intracellular 5′-O-(2-thiodiphosphate) trilithium salt inhibited the effect of sigma receptors on K(+) channels, which suggests that the signal transduction pathway does not involve a diffusible cytosolic second messenger or a G protein. Together, these data suggest that sigma-1 receptors are directly coupled to K(+) channels in intracardiac neurons. Furthermore, activation of sigma-1 receptors depresses the excitability of intracardiac neurons and is thus likely to block parasympathetic input to the heart.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15764734&dopt=Abstract
Differential neuronal localizations and dynamics of phosphorylated and unphosphorylated type 1 inositol 1,4,5-trisphosphate receptors.
Type 1 inositol 1,4,5-trisphosphate receptors are phosphorylated by cyclic-AMP-dependent protein kinase A at serines 1589 and 1755, with serine 1755 phosphorylation greatly predominating in the brain. Inositol 1,4,5-trisphosphate receptor protein kinase A phosphorylation augments Ca(2+) release. To assess type 1 protein kinase A phosphorylation dynamics in the intact organism, we developed antibodies selective for either serine 1755 phosphorylated or unphosphorylated species. Immunohistochemical studies reveal marked variation in localization. For example, in the hippocampus the phosphorylated type 1 inositol 1,4,5-trisphosphate receptor is restricted to CA1, while the unphosphorylated receptor occurs ubiquitously in CA1-CA3 and dentate gyrus granule cells. Throughout the brain the phosphorylated type 1 inositol 1,4,5-trisphosphate receptor is selectively enriched in dendrites, while the unphosphorylated receptor predominates in cell bodies. Focal cerebral ischemia in rats and humans is associated with dephosphorylation of type 1 inositol 1,4,5-trisphosphate receptors, and glutamatergic excitation of cerebellar Purkinje cells mediated by ibogaine elicits dephosphorylation of type 1 inositol 1,4,5-trisphosphate receptors that precedes evidence of excitotoxic neuronal degeneration.We have demonstrated striking variations in regional and subcellular distribution of inositol 1,4,5-trisphosphate receptor phosphorylation that may influence normal physiological intracellular Ca(2+) signaling in rat and human brain. We have further shown that the subcellular distribution of inositol 1,4,5-trisphosphate receptor phosphorylation in neurons is regulated by excitatory neurotransmission, as well as excitotoxic insult and neuronal ischemia-reperfusion. Phosphorylation dynamics of type 1 inositol 1,4,5-trisphosphate receptors may modulate intracellular Ca(2+) release and influence the cellular response to neurotoxic insults.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11166129&dopt=Abstract
Fluoro-Jade and silver methods: application to the neuropathology of scrapie, a transmissible spongiform encephalopathy.
Traditional methods for evaluating neurodegeneration include variations of Nauta’s selective silver-staining techniques. The Fluoro-Jade (FJ) method applies a novel fluorescent, anionic stain for localizing degenerating neurons. FJ has produced comparable results to the silver methods, when both have been applied to detect neurodegeneration in animals treated acutely with a variety of neurotoxins, including kainic acid (KA), ibogaine (IBO), 3-nitropropionic acid (3-NPA), domoic acid and others. The potential value of methods selective for neurodegeneration in elucidating the pathophysiology of transmissible spongiform encephalopathies (TSEs), such as the prion disease ‘scrapie’, has not yet been investigated. Using frozen or paraffin sections stained with FJ or silver, we evaluated the brains of hamsters inoculated with either the 263K or the 139H strains of scrapie, originally passaged from sheep into mice and then into hamsters. As a positive control, we also examined sections from IBO-treated rats, which experience degeneration restricted to small clusters of Purkinje neurons located in the paravermal region of the cerebellum. As expected, both FJ and silver methods delineated this identical pattern of neurodegeneration, characteristic of IBO exposure. Surprisingly, only a small number of FJ or silver-labeled cortical neurons were observed in scrapie-infected hamsters evaluated near the end of their incubation period but before obvious spongiform pathology. Instead, there was intense fluorescent staining of astrocytes in scrapie-infected hamsters, especially in the cortex, corpus callosum, and hypothalamus. Detailed protocols describing the application of the degeneration-selective methods we utilized are presented and compared.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11673092&dopt=Abstract
Modulation of high alcohol drinking in the inbred Fawn-Hooded (FH/Wjd) rat strain: implications for treatment.
The Fawn-Hooded rat (FH/Wjd) is an inbred alcohol-preferring rat strain, unlike most of the other strains that were selectively bred for high alcohol intake and preference. It was chosen for study some 16 years ago because of a reported mutation that disrupted platelet serotonin function. Although the FH/Wjd rat has high alcohol intake (>5 g/kg/day) and preference (>65%), interbreeding with an alcohol-non-preferring inbred strain suggested that these measures are unrelated to the serotonin abnormality. Similarly, the exaggerated immobility of the FH/Wjd rats in the forced swim test did not correlate with the high alcohol intake. Many compounds have been tested in the FH/Wjd rats after both acute and chronic treatment and a substantial number of them have proved effective. However, as the case with opiate antagonists, tolerance to the effects of the drug can develop. An up-regulation of opioid receptors accompanied the chronic treatment and this mechanism may account for the development of tolerance. Tolerance to opiate antagonists has also been demonstrated in two of the selectively bred alcohol-preferring rat lines, but it is unknown whether this process may contribute to the relapses seen in individuals being treated with naltrexone. Other drugs that reliably decrease alcohol intake in the FH/Wjd rats include the 5-hydroxytryptamine-2A receptor antagonist, amperozide, the mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and herbal derivatives such as ibogaine, St. John’s wort and kudzu extract. Thus, studies in the FH/Wjd rat have led to the discovery of a wide variety of targets for the development of novel agents to treat alcoholism. The fact that several of these drugs were shown to reduce alcohol intake in some of the selectively bred alcohol-preferring rat lines and/or alcohol-preferring vervet monkeys increases our confidence that they are good candidates for further development.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16961764&dopt=Abstract
Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment.
1: Pharmacol Biochem Behav. 2003 Jun;75(3):607-18. Related Articles, LinkOut Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Maisonneuve IM , Glick SD . Center for Neuropharmacology and Neuroscience, Albany Medical College, MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA. maisoni@mail.amc.edu 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity. Publication Types: Comparative Study Research Support, U.S. Gov’t, P.H.S.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12895678&dopt=Abstract
“Returning to the path”: the use of iboga[ine] in an equatorial African ritual context and the binding of time, space, and social relationships.
1: Alkaloids Chem Biol. 2001;56:235-47. Related Articles, LinkOut “Returning to the path”: the use of iboga[ine] in an equatorial African ritual context and the binding of time, space, and social relationships. Fernandez JW , Fernandez RL . Department of Anthropology, University of Chicago, Chicago, IL 60637, USA. Publication Types: Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S. Review
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705111&dopt=Abstract
Liquid chromatographic/mass spectrometric determination of biologically active alkaloids in extracts of Peschiera fuschiaefolia.
1: J Mass Spectrom. 2002 Feb;37(2):216-22. Related Articles, LinkOut Liquid chromatographic/mass spectrometric determination of biologically active alkaloids in extracts of Peschiera fuschiaefolia. Lepine F , Milot S , Zamir L , Morel R . Centre de Microbiologie et Biotechnologie, INRS-Institut Armand-Frappier, Universite du Quebec, 531 desPrairies blvd, Laval, Quebec H7V 1B7, Canada. francois.lepine@inrs.iaf.uquebec.ca Four alkaloids were isolated from an alcoholic extract of the bark from the stem of Peschiera fuschiaefolia. Two of these compounds, voacamine and voacamidine, are dimeric alkaloids which are thought to be responsible for the antimalarial activity of these extracts. The mass spectra and the response factors of these four compounds were obtained by liquid chromatography/mass spectrometry in the electrospray positive ionization mode. The concentrations of these alkaloids were measured in two different P. fuschiaefolia extracts. The ion chromatograms of the two extracts were compared on the basis of their [M + H](+) and [M + 2H](+2) ions characteristic of various alkaloids previously isolated from P. fuschiaefolia bark. The two extracts were found to differ mostly in the relative concentrations of the dimeric alkaloids. Copyright 2002 John Wiley & Sons, Ltd.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11857766&dopt=Abstract
Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration.
1: Eur J Pharmacol. 2004 May 25;492(2-3):159-67. Related Articles, LinkOut Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration. Pace CJ , Glick SD , Maisonneuve IM , He LW , Jokiel PA , Kuehne ME , Fleck MW . Center for Neuropharmacology and Neuroscience, The Albany Medical College, MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA. 18-Methoxycoronaridine, a novel iboga alkaloid congener, reduces drug self-administration in animal models of addiction. Previously, we proposed that these effects are mediated by the ability of 18-methoxycoronaridine to inhibit nicotinic alpha3beta4 acetylcholine receptors. In an attempt to identify more potent 18-methoxycoronaridine analogs, we have tested a series of 18-methoxycoronaridine congeners by whole-cell patch clamp recording of HEK 293 cells expressing recombinant nicotinic alpha3beta4 receptors or glutamate NR1/NR2B N-methyl-d-aspartate (NMDA) receptors. The congeners exhibited a range of inhibitory potencies at alpha3beta4 receptors. Five congeners had IC(50) values similar to 18-methoxycoronaridine, and all of these were ineffective at NMDA receptors. The congeners also retained their ability to reduce morphine and methamphetamine self-administration. These data are consistent with the importance of nicotinic alpha3beta4 receptors as a therapeutic target to modulate drug seeking. These compounds may constitute a new class of synthetic agents that act via the nicotinic alpha3beta4 mechanism to combat addiction. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15178360&dopt=Abstract
18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats.
1: Eur J Pharmacol. 2006 May 10;537(1-3):94-8. Epub 2006 Mar 24. Related Articles, LinkOut 18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats. Glick SD , Ramirez RL , Livi JM , Maisonneuve IM . Center for Neuropharmacology and Neuroscience Albany Medical College, MC-136, 47 New Scotland Avenue, NY 12208, USA. glicks@mail.amc.edu The novel iboga alkaloid congener 18-methoxycoronaridine (18-MC) is a putative anti-addictive agent that has been shown, in rats, to decrease the self-administration of morphine and other drugs of abuse. Previous work has established that 18-MC is a potent antagonist at alpha3beta4 nicotinic receptors. Because alpha3beta4 nicotinic receptors in the brain are preferentially located in the medial habenula and the interpeduncular nucleus, the present study was conducted to determine if 18-MC could act in these brain areas to modulate morphine self-administration in rats. Local administration of 18-MC into either the medial habenula or the interpeduncular area decreased morphine self-administration while having no effect on responding for a non-drug reinforcer (sucrose). Similar results were produced by local administration into the same brain areas of two other alpha3beta4 nicotinic antagonists, mecamylamine and alpha-conotoxin AuIB. Local administration of 18-MC into the ventral tegmental area had no effect on morphine self-administration. These and other data are consistent with the hypothesis that 18-MC decreases morphine self-administration by blocking alpha3beta4 nicotinic receptors in the habenulo-interpeduncular pathway. Publication Types: Comparative Study Research Support, N.I.H., Extramural
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16626688&dopt=Abstract
18-Methoxycoronaridine differentially alters the sensitized behavioral and dopaminergic responses to repeated cocaine and morphine administration. Implications for sensitization in the mediation of drug addiction.
1: Ann N Y Acad Sci. 2000;909:275-9. Related Articles, LinkOut 18-Methoxycoronaridine differentially alters the sensitized behavioral and dopaminergic responses to repeated cocaine and morphine administration. Implications for sensitization in the mediation of drug addiction. Szumlinski KK , Maisonneuve IM , Glick SD . Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA. szumlik@mail.amc.edu
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=10911941&dopt=Abstract
Antileishmanial activity of an indole alkaloid from Peschiera australis.
1: Antimicrob Agents Chemother. 2001 May;45(5):1349-54. Related Articles, Cited Articles, Free in PMC, Cited in PMC, LinkOut Antileishmanial activity of an indole alkaloid from Peschiera australis. Delorenzi JC , Attias M , Gattass CR , Andrade M , Rezende C , da Cunha Pinto A , Henriques AT , Bou-Habib DC , Saraiva EM . Laboratorio de Imunobiologia das Leishmanioses, Departamento de Imunologia-Instituto de Microbiologia, Rio de Janeiro, RJ, Brazil. In this study, we show the leishmanicidal effects of a chloroform fraction (CLF) and a purified indole alkaloid obtained from crude stem extract of Peschiera australis against Leishmania amazonensis, a causative agent of cutaneous leishmaniasis in the New World. In a bioassay-guided chemical fractionation, the leishmanicidal activity in CLF completely and irreversibly inhibited promastigote growth. This fraction was also active against amastigotes in infected murine macrophages. Chemical analysis of CLF identified an iboga-type indole alkaloid coronaridine as one of its major compounds. Coronaridine showed potent antileishmanial activity, inhibiting promastigote and amastigote growth. Promastigotes and amastigotes treated with CLF or coronaridine showed pronounced alterations in their mitochondria as assessed by transmission electron microscopy. Publication Types: Research Support, Non-U.S. Gov’t
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11302794&dopt=Abstract
In vitro activities of iboga alkaloid congeners coronaridine and 18-methoxycoronaridine against Leishmania amazonensis.
1: Antimicrob Agents Chemother. 2002 Jul;46(7):2111-5. Related Articles, Cited Articles, Free in PMC, Cited in PMC, LinkOut In vitro activities of iboga alkaloid congeners coronaridine and 18-methoxycoronaridine against Leishmania amazonensis. Delorenzi JC , Freire-de-Lima L , Gattass CR , de Andrade Costa D , He L , Kuehne ME , Saraiva EM . Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. In previous studies, we demonstrated the leishmanicide effect of coronaridine, a natural indole alkaloid isolated from stem bark of Peschiera australis (Delorenzi et al., Antimicrob. Agents Chemother. 45:1349-1354, 2001). In this study we show the leishmanicidal effect of the synthetic coronaridine and its racemic 18-methoxylated analog, 18-methoxycoronaridine. Both alkaloids revealed a potent leishmanicide effect against Leishmania amazonensis, a causative agent of cutaneous and diffuse cutaneous leishmaniasis in the New World. Despite their potent leishmanicide effect, both alkaloids were neither toxic to murine macrophages nor did they modulate their oxidative or cytokine production responses. Publication Types: Research Support, Non-U.S. Gov’t
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12069962&dopt=Abstract
18-MC reduces methamphetamine and nicotine self-administration in rats.
1: Neuroreport. 2000 Jun 26;11(9):2013-5. Related Articles, LinkOut 18-MC reduces methamphetamine and nicotine self-administration in rats. Glick SD , Maisonneuve IM , Dickinson HA . Center for Neuropharmacology and Neuroscience, Albany Medical College, NY 12208, USA. In previous studies, 18-methoxycoronaridine (18-MC), a novel iboga alkaloid congener, has been found to decrease the intravenous self-administration of morphine and cocaine in rats. In the present study, 18-MC (1-40 mg/kg, i.p.) dose-dependently decreased the i.v. self-administration of methamphetamine and nicotine. As in the previous studies, drug self-administration was reduced for > or = 24 h after the highest dose of 18-MC. A comparison of 18-MC’s interactions with all four drugs of abuse studied so far indicated that 18-MC is least effective in decreasing methamphetamine self-administration and most potent in decreasing nicotine self-administration. The results suggest that a nicotinic antagonist action of 18-MC contributes to its putative anti-addictive efficacy. Publication Types: Research Support, U.S. Gov’t, P.H.S.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=10884062&dopt=Abstract
Anti-HIV-1 activity of the Iboga alkaloid congener 18-methoxycoronaridine.
1: Planta Med. 2004 Sep;70(9):808-12. Related Articles, LinkOut Anti-HIV-1 activity of the Iboga alkaloid congener 18-methoxycoronaridine. Silva EM , Cirne-Santos CC , Frugulhetti IC , Galvao-Castro B , Saraiva EM , Kuehne ME , Bou-Habib DC . Laboratorio Avancado de Saude Publica, Centro de Pesquisas Goncalo Moniz, Salvador, BA, Brazil. The Iboga alkaloid congener 18-methoxycoronaridine (18-MC) exhibits in vitro leishmanicidal and in vivo anti-addiction properties. In this paper, we describe that 18-MC inhibits HIV-1 infection in human peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages. We found that 18-MC inhibits the replication of primary isolates of HIV-1 in a dose-dependent manner, regardless of the preferential chemokine receptor usage of the isolates, at non-cell-toxic concentrations. The antiretroviral activity of 18-MC resulted in EC (50) values of 22.5 +/- 4.7 microM and 23 +/- 4.5 microM for R5 and X4 isolates, respectively, in PBMCs, and a therapeutic index (TI) of 14.5. Similar findings were observed for inhibition of HIV-1 replication in macrophages: EC (50) equal to 12.8 +/- 5 microM and 9.5 +/- 3 microM for an R5 virus after 14 and 21 days of infection, respectively, with TI equal to 25.6 and 34.5. 18-MC moderately inhibits the HIV-1 enzyme reverse transcriptase (IC (50) = 69.4 microM), which at least partially explains its antiretroviral activity. Publication Types: Research Support, Non-U.S. Gov’t
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15386189&dopt=Abstract
Voacamine, an alkaloid extracted from Peschiera fuchsiaefolia, inhibits P-glycoprotein action in multidrug-resistant tumor cells.
1: Int J Oncol. 2005 Dec;27(6):1597-603. Related Articles, LinkOut Voacamine, an alkaloid extracted from Peschiera fuchsiaefolia, inhibits P-glycoprotein action in multidrug-resistant tumor cells. Meschini S , Marra M , Condello M , Calcabrini A , Federici E , Dupuis ML , Cianfriglia M , Arancia G . Department of Technology and Health, Italian National Institute of Health, I-00161 Rome, Italy. Multidrug resistance (MDR) in tumor cells is generally associated with increased efflux of the cytotoxic compounds, due to the activation of mechanisms of intracellular transport and to the overexpression of surface proteins, such as P-glycoprotein (Pgp), which act as ATP-dependent molecular pumps. In a previous study, voacamine, a bisindolic alkaloid from Peschiera fuchsiaefolia, was examined for its possible capability of enhancing the cytotoxic effect of doxorubicin (DOX) on resistant human osteosarcoma cells. The effects of voacamine on the cell survival and on accumulation of DOX were investigated on both the parental cell line, U-2 OS-WT, and its resistant counterpart, U-2 OS-R. A differential effect between sensitive and resistant cells on the intracellular DOX concentration and distribution was revealed. In particular, voacamine induced a significant increase of drug retention and intranuclear location in resistant cells. Moreover, the cell survival analysis and the electron microscopic observations revealed an enhancement of the cytotoxic effect of DOX induced by the plant extract. In the present study, a panel of monoclonal antibodies (MAbs), recognizing different and specific structural and functional state of Pgp, was used. By flow cytometry and immunofluorescence confocal microscopy, a dose-dependent increase of the reactivity of Pgp with MAb UIC2, which specifically recognizes an epitope of the drug transporter in its functional conformation, was detected in voacamine-treated U-2 OS-R cells. Conversely, the expression of the epitope recognized by MAb MC57 was downregulated while MAb MM4.17 did not change its binding level to treated and untreated MDR cells. These data suggest that the plant extract reacts with Pgp producing conformational changes with consequent epitope modulation. Taken together, our observations seem to demonstrate that voacamine is a substrate for Pgp and, therefore, interferes with the Pgp-mediated drug export, acting as a competitive antagonist of cytotoxic agents. Publication Types: Research Support, Non-U.S. Gov’t
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16273216&dopt=Abstract
Psychotropic complementary medicines.
1: Br J Psychiatry. 2006 Jun;188:587; author reply 587-8. Related Articles, LinkOut Comment on: Br J Psychiatry. 2006 Feb;188:109-21. Psychotropic complementary medicines. Alper KR , Glick SD . Publication Types: Comment Letter
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16738355&dopt=Abstract
Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents.
1: J Med Chem. 2003 Jun 19;46(13):2716-30. Related Articles, LinkOut Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents. Kuehne ME , He L , Jokiel PA , Pace CJ , Fleck MW , Maisonneuve IM , Glick SD , Bidlack JM . Department of Chemistry, University of Vermont, Burlington, Vermont 05405, USA. mkuehne@zoo.uvm.edu Variation of the methoxycarbonyl and C-18 substituents of the antiaddictive compound 18-methoxycoronaridine, and contraction of its isoquinuclidine ring segment, provided 15 congeners for SAR evaluation at opioid and alpha3beta4 nicotinic acetylcholine receptors. The opioid activities were relatively low, and the alpha3beta4 nicotinic acetylcholine receptor activities were found to correlate with in vivo antiaddictive activities. Publication Types: Research Support, U.S. Gov’t, P.H.S.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12801235&dopt=Abstract
Doubts cast on antimalarial drug.
1: Lancet Infect Dis. 2003 Feb;3(2):61. Related Articles, Cited in PMC, LinkOut Doubts cast on antimalarial drug. Orellana C . Publication Types: News
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12560176&dopt=Abstract
Biologically active ibogan and vallesamine derivatives from Tabernaemontana divaricata.
1: Chem Biodivers. 2004 Apr;1(4):646-56. Related Articles, LinkOut Biologically active ibogan and vallesamine derivatives from Tabernaemontana divaricata. Kam TS , Pang HS , Choo YM , Komiyama K . Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. tskam@um.edu.my Six new indole alkaloids, viz., (3S)-3-cyanocoronaridine (2), (3S)-3-cyanoisovoacangine (3), conolobine A (5), conolobine B (6), conolidine (7), and (3R/3S)-3-ethoxyvoacangine (8), in addition to 36 known ones, were obtained from the stem-bark extract of the Malayan Tabernaemontana divaricata. The structures were determined by NMR and MS analysis. The CN-substituted alkaloids showed appreciable cytotoxicity towards the KB human oral epidermoid carcinoma cell-line. Publication Types: Research Support, Non-U.S. Gov’t
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=17191876&dopt=Abstract
Sigma receptors and iboga alkaloids.
1: Alkaloids Chem Biol. 2001;56:173-91. Related Articles, LinkOut Sigma receptors and iboga alkaloids. Bowen WD . Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Publication Types: Review
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705107&dopt=Abstract
GDNF and addiction.
1: Rev Neurosci. 2005;16(4):277-85. Related Articles, LinkOut GDNF and addiction. Ron D , Janak PH . Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, USA. dorit@itsa.ucsf.edu Biochemical adaptations to drugs of abuse and alcohol are especially profound in midbrain dopaminergic neurons. Long-lasting molecular and structural changes in mesolimbic dopaminergic neurons that result from chronic exposure to drugs of abuse and alcohol are thought to underlie adverse behaviors such as compulsive drug seeking and relapse. Recent studies suggest that a subset of these changes is prevented/reversed by activation of the glial cell line-derived neurotrophic factor (GDNF) signaling pathway. Behavioral effects of drugs of abuse such as cocaine and alcohol are also negatively regulated by GDNF: inhibition of the endogenous GDNF pathway enhances the activity of drugs of abuse, while administration of GDNF reduces the severity of the effects. In this review, we summarize the data implicating GDNF as a negative regulator of drug and alcohol addiction. We also provide evidence to suggest that therapies that activate GDNF signaling may be useful for the treatment of drug and alcohol addiction. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S. Review
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16519005&dopt=Abstract
Cytotoxic effects and reversal of multidrug resistance by ibogan and related indole alkaloids.
1: Bioorg Med Chem Lett. 2004 Sep 6;14(17):4487-9. Related Articles, LinkOut Cytotoxic effects and reversal of multidrug resistance by ibogan and related indole alkaloids. Kam TS , Sim KM , Pang HS , Koyano T , Hayashi M , Komiyama K . Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. tskam@um.edu.my A series of indole alkaloids of the ibogan-type was assessed for their cytotoxic effects as well as their potential in reversing MDR in vincristine-resistant KB cells. Of a total of 25 compounds tested, 3(S)-cyanocoronaridine, 3(S)-cyanoisovoacangine, 3(S)-cyanovoacangine, and 10,11-demethoxychippiine were found to show appreciable cytotoxicity toward KB cells, while coronaridine, heyneanine, 19-epi-heyneanine, dippinine B, and dippinine C, were found to reverse MDR in vincristine-resistant KB cells. Publication Types: Research Support, Non-U.S. Gov’t
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=15357977&dopt=Abstract
Natural medicines for alcoholism treatment: a review.
1: Drug Alcohol Rev. 2005 Nov;24(6):525-36. Related Articles, LinkOut Comment in: Drug Alcohol Rev. 2005 Nov;24(6):473. Natural medicines for alcoholism treatment: a review. Xu BJ , Zheng YN , Sung CK . Department of Food Science and Technology, College of Agriculture and Biotechnology, Chungnam National University, Daejon, South Korea. Alcoholism is a serious problem throughout the world. The development of alcoholism remedies have medical, social and economical significance. In view of the pitfalls of psychological dependence and adverse behavioural effects of synthetic drugs, the development of low toxicity and high efficiency medicines derived from natural products exhibits expansive market prospects. Based on these considerations, we summarize briefly folk application of traditional hangover remedies and clinical application of herbal complex and patent medicines for alcoholism treatment. We have reviewed the effects of natural medicines on intake, absorption and metabolism of alcohol, as well as the protective effects on alcohol-induced acute and chronic tissue injury. Publication Types: Review
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=16361209&dopt=Abstract
18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens.
1: Synapse. 2007 Jul;61(7):547-60. Related Articles, LinkOut 18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens. Taraschenko OD , Shulan JM , Maisonneuve IM , Glick SD . Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208, USA. tarasco@mail.amc.edu 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, is a potential treatment for drug addiction. 18-MC has been shown to decrease self-administration of drugs (e.g., morphine, methamphetamine, nicotine) and attenuate opioid withdrawal in rats. In previous studies, systemic pretreatment with 18-MC abolished the sensitized increase in accumbens dopamine levels induced by chronic morphine administration. In vitro studies have shown that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors, and alpha3beta4 antagonism is believed to be the primary mechanism responsible for 18-MC’s effects on drug self-administration and possibly on morphine-induced changes in mesolimbic dopamine. While there are very low densities of alpha3beta4 nicotinic receptors in the mesolimbic pathway, these receptors are prominently localized in the medial habenula (MHb) and in the interpeduncular nucleus (IPN). These nuclei and the habenulo-interpeduncular pathway connecting them are believed to function as part of an alternate reward pathway modulating the dopaminergic mesolimbic pathway known to be involved in drug addiction. In the present study, to determine if 18-MC acts in the MHb or in the IPN, the effects of local infusion of 18-MC into these brain areas were assessed on mesolimbic dopamine responses to acute and repeated morphine treatment. Administration of 18-MC (10 mug) into either the IPN or MHb blocked the sensitized dopamine response to repeated morphine in the nucleus accumbens; 18-MC had no effect on the dopamine response to acute morphine. The results suggest that 18-MC acts in the habenulo-interpeduncular pathway to modulate the effects of repeated morphine in the dopaminergic mesolimbic system.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=17447255&dopt=Abstract
Addiction treatment strives for legitimacy.
1: JAMA. 2002 Dec 25;288(24):3096, 3099-101. Related Articles, Cited in PMC, LinkOut Addiction treatment strives for legitimacy. Vastag B . Publication Types: News
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=12495380&dopt=Abstract
Biological activities of the plant-derived bisindole voacamine with reference to malaria.
1: Phytother Res. 2001 Feb;15(1):30-3. Related Articles, LinkOut Biological activities of the plant-derived bisindole voacamine with reference to malaria. Ramanitrahasimbola D , Rasoanaivo P , Ratsimamanga-Urverg S , Federici E , Palazzino G , Galeffi C , Nicoletti M . Laboratoire de Phytochimie et de Pharmacologie Cellulaire et Parasitaire, Institut Malgache de Recherches Appliquees, B. P. 3833, 101-Antananarivo, Madagascar. The in vivo antiplasmodial activity of voacamine was assessed in a 4-day test. It was shown to exhibit in vivo activity with 25.4% and 43.4% inhibition of parasitaemia with 2.5 and 10 mg/kg, respectively. In synchronized cultures, it was found to act on trophozoite and schizont stages of Plasmodium falciparum. Using the FMC29 strain of Plasmodium falciparum as parasite and the isobologram curve as a method to assess interaction in drug combination, it was shown to lack any chloroquine-enhancing activity and its in vitro antiplasmodial effect was not potentiated by the chemosensitizer malagashanine. Copyright -Copyright 2001 John Wiley & Sons, Ltd.
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=11180519&dopt=Abstract
Treatment of allergic rhinitis: H1-antihistamines and intranasal steroids.
1: Curr Drug Targets Inflamm Allergy. 2002 Sep;1(3):215-20. Related Articles, LinkOut Treatment of allergic rhinitis: H1-antihistamines and intranasal steroids. Wang DY . Department of Otolaryngology, National University of Singapore. entwdy@nus.edu.sg Allergic rhinitis is charterized as an inflammatory disease of the nasal mucosa. In clinical practice, H(1)-antihistamines and topical corticosteroids are most commonly used pharmacological agents for the treatment of allergic rhinitis. The beneficial effects of steroids depend upon their long-term anti-inflammatory effect rather than upon direct receptor antagonism. This is different to H(1)-antihistamines, which block both neural and vascular H(1) receptors and have a clinical effect on symptoms such as nasal itching, sneezing, and rhinorrhea. H(1)-antihistamines are rapidly absorbed and most of them are metabolized by the hepatic cytochrome P system and begin to reduce nasal symptoms (itching and sneezing) within one hour. Understanding of both the efficacy and the pharmacological properties of these commonly used drugs in the treatment of nasal allergic inflammation and its related nasal symptoms is very important. From a clinical viewpoint, it will provide a useful guideline for an appropriate use of these drugs. Publication Types: Review
http://www.ncbi.nlm.nih.gov:80/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=14561186&dopt=Abstract

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