Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations.

The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50-100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40-60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

Increase in ENHANCER OF SHOOT REGENERATION2 expression by treatment with strigolactone-related inhibitors and kinetin during adventitious shoot formation in ipecac.

KEY MESSAGE: Increase of ENHANCER OF SHOOT REGENERATION 2 expression was consistent to treatment with kinetin, TIS108, and KK094 in adventitious shoot formation of ipecac. Unlike many plant species, ipecac (Carapichea ipecacuanha (Brot.) L. Andersson) can form adventitious shoots in tissue culture without cytokinin (CK) treatment. Strigolactone (SL) biosynthesis and signaling inhibitors stimulate adventitious shoot formation in ipecac, suggesting their potential use as novel growth regulators in plant tissue culture, but the molecular mechanism of their action is unclear. In this study, we compared the effects of SL-related inhibitors (TIS108 and KK094) and CKs (2iP, tZ, and kinetin) on adventitious shoot formation in ipecac. Exogenously applied SL-related inhibitors and CKs stimulated adventitious shoot formation. Combinations of SL-related inhibitors and kinetin also promoted adventitious shoot formation, but without additive effects. We also analyzed the expression of CK biosynthesis genes in ipecac. TIS108 increased the expression of the ipecac homolog of ISOPENTENYL TRANSFERASE 3 (CiIPT3) but decreased that of LONELY GUY 7 homolog (CiLOG7), presumably resulting in no change in 2iP-type CK levels. KK094 and kinetin increased CiLOG7 expression, elevating 2iP-type CK levels. Among pluripotency- and meristem-related genes, TIS108, KK094, and kinetin consistently increased the expression of ENHANCER OF SHOOT REGENERATION 2 homolog (CiESR2), which has a key role in shoot regeneration, in the internodal segment region that formed adventitious shoots. We propose that CiESR2 might be a key stimulator of adventitious shoot formation in ipecac.

Ipecac root extracts and isolated circular peptides differentially suppress inflammatory immune response characterised by proliferation, activation and degranulation capacity of human lymphocytes in vitro.

Circular peptides are attractive lead compounds for drug development; this study investigates the immunomodulatory effects of defined root powder extracts and isolated peptides (called cyclotides) from Carapichea ipecacuanha (Brot.) L. Andersson ('ipecac'). Changes in the viability, proliferation and function of activated human primary T cells were analysed using flow cytometry-based assays. Three distinct peptide-enriched extracts of pulverised ipecac root material were prepared via C18 solid-phase extraction and analysed by reversed-phase HPLC and mass spectrometry. These extracts induced caspase 3/7 dependent apoptosis, thus leading to a suppressed proliferation of activated T cells and a reduction of the number of cells in the G2 phase. Furthermore, the stimulated T cells had a lower activation potential and a reduced degranulation capacity after treatment with ipecac extracts. Six different cyclotides were isolated from C. ipecacuanha and an T cell proliferation inhibiting effect was determined. Furthermore, the degranulation capacity of the T cells was diminished specifically by some cyclotides. In contrast to kalata B1 and its analog T20K, secretion of IL-2 and IFN- γ was not affected by any of the caripe cyclotides. The findings add to our increased understanding of the immunomodulating effects of cyclotides, and may provide a basis for the use of ipecac extracts for immunomodulation in conditions associated with an exessive immune responses.

Attenuation of brain mitochondria oxidative damage by Albizia julibrissin Durazz: neuroprotective and antiemetic effects.

Medicinal plants, as new drugs, are considered for treatment of insomnia, anxiety, depression, confusion, nausea, and vomiting symptoms. The current study aimed to evaluate the neuroprotective and antiemetic effects of Albizia. julibrissin Durazz. flower extract in the chickens. Emesis was induced by copper sulfate and ipecac (60 and 600 mg/kg, orally, respectively) and the methanolic extract (50, 100, and 200 mg/kg) were injected intraperitoneally (i.p.). Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC) content, and catalase activity as biomarkers of oxidative damage were evaluated in the brain mitochondria. All doses of extract showed significant (p < 0.001) antiemetic activity against induced emesis by copper sulfate and ipecac. Brain mitochondria function (by 50, 100, and 200 mg/kg of extract) were increased 48%, 85%, and 90% against emesis induced by ipecac and 32%, 18%, and 24% against emesis induced by copper sulfate, respectively. LPO and PC contents were significantly decreased after the administration of extract in emesis induced by copper sulfate and ipecac. A significant decrease (p < 0.01) of CAT activity was observed in the extract (200 mg/kg) group in emesis induced by copper sulfate in chickens brain mitochondria. The present study suggests that the extract had antiemetic effects against emesis induced by copper sulfate and ipecac in young chickens via peripheral and central mechanisms. Neuroprotective effect of the extract could be due to the increase in bioactive compounds, plasma antioxidants, or direct free radical scavenging that could prevent lipid and protein alteration and impede the formation of oxidative damage.

hERG Channel Blocking Ipecac Alkaloids Identified by Combined In Silico - In Vitro Screening.

Human ether-a-go-go-related gene channel blocking is associated with QT interval prolongation and increased risk of potentially fatal arrhythmias. As natural products keep increasing in popularity, there is an urgent need for studies assessing human ether-a-go-go-related gene channel-related cardiotoxic risks. We selected 49 plant species based on the results of a pharmacophore-based virtual screening campaign, in parallel with a literature data survey concerning highly consumed herbal medicines with reported cardiac liabilities. Lead-like enhanced extracts were prepared, an initial in vitro screening was performed at 100 µg/mL by voltage clamp on Xenopus oocytes, and five human ether-a-go-go-related gene channel blocking extracts were identified. In accordance to the six virtually predicted alkaloids, the root extract of Carapichea ipecacuanha inhibited human ether-a-go-go-related gene channel currents by 32.5 %. A phytochemical workflow resulted in the isolation and identification of five out of the six virtually predicted alkaloids. All isolates blocked human ether-a-go-go-related gene channel currents to different extents. The major ipecac constituents emetine (1) and cephaeline (2) showed IC50 values of 21.4 and 5.3 µM, respectively, measured by whole-cell patch clamp in HEK293 cells. This is the first report on human ether-a-go-go-related gene channel blockers from C. ipecacuanha. Its roots and rhizomes are used to produce different pharmacopeial ipecac preparations that are mainly used as emetics for poisoning treatment. Our findings raise further questions regarding the safety and over-the-counter appropriateness of these herbal products.

Impact of a working group on gastrointestinal decontamination in Spanish emergency departments.

INTRODUCTION AND OBJECTIVES: The aim of this study is to analyze the impact of the actions carried out by the Intoxications Working Group (IWG) of Spanish Society of Pediatric Emergencies in the management of acute pediatric intoxications in Spain, specifically the publishing of a Handbook in 2004 or the creation of the Toxicologic Surveillance System in 2009. PATIENTS AND METHODS: Gastrointestinal decontamination procedures were analyzed in three periods of time in Pediatric Emergency Departments (PEDs) included in the IWG: group A (2001-2002, 17 PED, 2157 episodes), group B (2008-2009, 22 PED, 612 episodes), and group C (2009-2011, 42 PED, 400 episodes). These periods were chosen because the main actions of the IWG were developed in the time in-between them. RESULTS: Of the 3169 episodes included, a gastrointestinal decontamination procedure was performed in 1031. The use of ipecac syrup decreased from 22.8% in group A to 0 in group C and the performance of a gastric lavage decreased from 29.1% in group A to 26% in group C (NS), although on splitting yearly patients of group C, it decreased to 14.7% in 2011. CONCLUSION: Recommendations developed and spread by a Working Group have approached the management of acute pediatric intoxications in Spain to international guidelines on the basis of scientific evidence.

Studies for the emetic mechanisms of ipecac syrup (TJN-119) and its active components in ferrets: involvement of 5-hydroxytryptamine receptors.

Ipecac syrup, prepared from a galentical ipecac, contains the nauseant alkaloids cephaeline and emetine. The involvement of receptors and serotonin- and dopamine-metabolizing enzymes in the emesis induced by ipecac syrup and these components was investigated. 1) In ferrets, the selective 5-HT3-receptor antagonist ondansetron (0.5 mg/kg, p.o.) prevented each emesis induced by TJN-119 (0.5 mL/kg, p.o.), cephaeline (0.5 mg/kg, p.o.) and emetine (5.0 mg/kg, p.o.), but the intraperitoneal administration of the selective dopamine D2-receptor antagonist sulpiride failed to significantly suppress the TJN-119, cephaeline and emetine-induced emesis at a dose of 0.1 mg/kg that blocked apomorphine-induced emesis. 2) In the receptor binding assays, cephaeline and emetine had a distinct affinity to 5-HT4 receptor, but no or weak affinity to 5-HT1A, 5-HT3, nicotine, M3, beta1, NK1, and D2 receptors. 3) Cephaeline and emetine did not affect activities of metabolic enzymes of 5-HT and dopamine (MAO-A, MAO-B, tryptophan 5-hydroxylase and tyrosine hydroxylase) in vitro. These results suggest that 5-HT3 receptor plays an important role in the emetic action of TJN-119, cephaeline and emetine, and the 5-HT4 receptor may be involved in their mechanisms.

Pharmacological aspects of ipecac syrup (TJN-119)-induced emesis in ferrets.

In order to elucidate the precise mechanism of ipecac syrup (TJN-119) on the occurrence of vomiting, we examined the effects of ipecac syrup on the abdominal afferent nerve activity as well as on the 5-HT levels of the ileum and area postrema in ferrets. Oral administration of TJN-119 (0.5 mg/kg) produced a significant increase in afferent abdominal vagus nerve activity which lasted approximately 1 hour. The maximum response induced by TJN-119 was estimated to be 219 +/- 18% of the pre-injection level. Cephaeline or emetine, the main alkaloids of ipecac syrup, also demonstrated similar effects on afferent vagus nerve activity. TJN-119 increased the 5-HT content in the ileum but not in the area postrema. These observations illustrate possible mechanisms that may act at peripheral sites. It was recently reported that TJN-119 has a high affinity to 5-HT4 receptors (Hasegawa et al., unpublished data). These results suggest that 5-HT4 receptors may be involved in the emetic action of TJN-119.

5-HT3 receptors are not involved in conditioned taste aversions induced by 5-hydroxytryptamine, ipecacuanha or cisplatin.

We have used the rat to examine the involvement of the 5-HT3 receptor in the mechanism(s) of conditioned taste aversion induced by 5-hydroxytryptamine (5-HT) and selected emetic drugs. 5-HT, ipecacuanha and cisplatin all induced conditioned taste aversion at doses known to induce emesis in other species but the responses were resistant to treatment with the 5-HT3 receptor antagonists ondansetron and granisetron. Further, m-chlorophenylbiguanide, a selective and potent 5-HT3 receptor agonist, failed to induce a conditioned taste aversion. The data provide strong evidence that the 5-HT3 receptor is not involved in conditioned taste aversion mechanisms in the rat. Results are discussed in terms of the usefulness of the rat conditioned taste aversion paradigm to anti-emetic research.

Effects of propofol on ipecacuanha-induced nausea and vomiting.

BACKGROUND: The purpose of this study was to evaluate if propofol has 5-HT3 antagonistic effects. Ipecacuanha is known to release serotonin (5-HT) in the gastrointestinal tract and therefore ipecacuanha syrup was used to induce nausea and vomiting. The 5-HT3 antagonist ondansetron was used as a control substance. METHOD: Ten healthy male volunteers (20-37 years) were studied on three occasions and were randomly allocated to receive a concomitant infusion of propofol (initial bolus 0.1 mg kg(-1) then 1 mg kg(-1)h(-1)), ondansetron (initial bolus 0.11 mg kg(-1) then 14 microg kg(-1)h(-1)) and placebo on either occasion. The infusions started 30 min before oral ingestion of 30 ml of ipecacuanha and continued until 150 min after the intake. The number of retchings was recorded and the intensity of nausea was estimated by the subjects on a visual analog scale. RESULTS: During the first 150 min after ingestion of ipecacuanha there were no retchings during the ondansetron infusion (P=0.01 vs placebo, P=0.02 vs propofol) and significantly fewer retchings during propofol infusion compared to placebo (P<0.02). There was no nausea during the ondansetron infusion (P<0.01 vs placebo and propofol) but the volunteers experienced nausea both during the placebo and propofol infusion (NS). CONCLUSION: This study in volunteers has shown that propofol reduces the intensity of retching after oral intake of ipecacuanha syrup. As ipecacuanha releases 5-hydroxytryptamine, it can be concluded that propofol may have a weak 5-HT3 antagonistic effect.

Manejo inicial de intoxicaciones con jarabe ipeca, carbón activado y diálisis enteral / First management of ipeca syrup intoxication, active carbon and enteral dyalisis

Ya en el siglo XVI Paracelso escribió: cualquier sustancia puede ser tóxica y todo depende de la dosis administrada. La intoxicaciones son un motivo frecuente de consulta, el 82 por ciento de ellas se producen vía digestiva, el 70 por ciento del total son de tal gravedad, que requieren hospitalización y de éstas la mitad debe hacerlo en Unidades de Cuidados Intensivos

Effect of zatosetron on ipecac-induced emesis in dogs and healthy men.

Serotonin receptor (5-HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5-HT3 receptor antagonists also have antiemetic activity in ipecac-induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5-HT3 receptor antagonist, on ipecac-induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion in healthy men. In separate randomized, placebo-controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac-induced emesis in both groups. In dogs, zatosetron inhibited ipecac-induced emesis in a dose-dependent manner with a 100-micrograms/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5-HIAA/creatinine ratio (mg/g) or 5-HIAA excretion rate (microgram/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac-induced emesis in healthy men, as has been shown previously with other 5-HT3 receptor antagonists in chemotherapy-induced emesis in cancer patients. We did not observe the increase of urinary 5-HIAA in our study with ipecac-induced emesis, however, as has been described previously in cisplatin-induced emesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of time until emesis on the efficacy of decontamination using acetaminophen as a marker in a pediatric population.

STUDY OBJECTIVE: To determine the extent of drug removal by emesis at different times after the ingestion of a toxic substance. DESIGN: Multicenter retrospective chart review. METHODS: Using the American Association of Poison Control Centers' aggregate data base, children who had ingested acetaminophen and who were referred to a health care facility by one of 11 poison centers during a two-year period were identified. Charts of these patients were reviewed to determine the quantity ingested per kilogram of body weight, method of decontamination used, the timing of decontamination, and the serum acetaminophen concentration obtained four hours after ingestion. RESULT: Charts of 455 patients met all requirements for inclusion. When emesis occurred within one-half hour after ingestion, mean serum acetaminophen concentration drawn four hours after ingestion was approximately half that in a control group that received no decontamination. Emesis had less impact when it was delayed further and had no demonstrable impact when it occurred more than 90 minutes after ingestion. CONCLUSION: Many factors must be considered when deciding if and by what method a given patient should receive decontamination. When delayed gastric emptying is not expected, emesis can at best decrease a toxic burden by half if it occurs early. Medical care givers must continue to scrutinize management practice to ensure that syrup of ipecac is given only in situations in which it is likely to make a difference in outcome and in which it is the most effective agent to achieve this goal.

Evaluation of gastric emptying using radionuclides: gastric lavage versus ipecac-induced emesis.

STUDY OBJECTIVES: To compare the efficacy of gastric lavage and ipecac-induced emesis by using a radionuclide marker in a simulated overdose and to determine the amount of material recoverable after lavage fluid appears clear. DESIGN: Case-control, prospective cross-over study. SETTING: Nuclear medicine department of Valley Medical Center, Fresno, California. TYPE OF PARTICIPANTS: Fourteen male and five nonpregnant female adult volunteers with no pre-existing gastrointestinal disease and no medication use. INTERVENTIONS AND MEASUREMENTS: In phase 1, each volunteer ingested 30 capsules labeled with a measured amount of Tc99m with 75 mL H2O followed in five minutes by ipecac-induced emesis. In phase 2, two to four weeks later, each subject was lavaged after ingesting 30 labeled capsules. After lavage appeared clear, a 1,000-mL supplemental lavage was done and analyzed separately. All emesis or gastric lavage fluid was collected and measured for tracer activity. RESULTS: All subjects in the ipecac group vomited with an average time from ipecac to emesis of 19 minutes. Two subjects withdrew from the study, refusing to complete lavage due to discomfort. Based on retrieved material, ipecac-induced emesis returned significantly more tracer (mean +/- SD, 54.1 +/- 21.3%) than lavage until clear (mean +/- SD, 30.3 +/- 17.4%) (P = .0021). Supplemental lavage returned 12.9% of the total recovered marker (SD, 11.6%). The total of initial and supplemental returns from lavage was 35.5% (SD, 21.0%). This return was significantly less than that returned by ipecac-induced emesis (P = .016). CONCLUSION: In this study, ipecac-induced emesis was significantly more effective than gastric lavage in emptying the stomach after simulated overdose. Significant amounts of ingested material are recoverable in gastric lavage return after it appears clear.

Low-volume whole bowel irrigation and salicylate absorption: a comparison with ipecac-charcoal.

STUDY OBJECTIVE: To evaluate two methods of gastrointestinal decontamination, low-volume whole bowel irrigation (WBI) and activated charcoal, for their ability to prevent absorption of salicylate. DESIGN: Randomized, two-phase crossover study. SETTING: A clinical research unit in a university-based teaching hospital. PATIENTS: Six healthy, volunteer men. INTERVENTIONS: Subjects were assigned to receive 3000 ml WBI or syrup of ipecac 30 ml followed by activated charcoal 50 g in sorbitol, and were crossed over to the other treatment phase after 1 week. All treatments began 30 minutes after ingestion of 3.25 g aspirin. Urine was collected over 24 hours for analysis of total urinary excretion of salicylate. Serial blood samples were collected for salicylate determination and were subjected to pharmacokinetic analysis. MEASUREMENTS AND MAIN RESULTS: Mean +/- SD recovery of salicylate were WBI 48.6 +/- 5.4% and ipecac-charcoal 37.0 +/- 2.6% from urine (p < 0.01). CONCLUSION: Ipecac-charcoal produced a significantly lower salicylate absorption (peak concentration, AUC) than WBI (p < 0.01) and thus was superior to low-volume WBI.

Psychotrine and its O-methyl ether are selective inhibitors of human immunodeficiency virus-1 reverse transcriptase.

Psychotrine dihydrogen oxalate and O-methylpsychotrine sulfate heptahydrate (MP), the salts of isoquinoline alkaloids from ipecac, were found to be potent inhibitors of the DNA polymerase activity of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT). We currently report the results of additional studies designed to characterize the mechanism of inhibition facilitated by MP. The inhibition was noncompetitive with respect to TTP and uncompetitive with respect to poly(rA) and oligo(dT)12-18 (4:1) at low template-primer concentrations but competitive at high concentrations (greater than 200 microM). Identical non-Michaelis-type kinetics were observed when activated DNA was used as the template. The biphasic nature of the double-reciprocal plots and Hill coefficients of less than 1 indicate that MP functions as an allosteric inhibitor of the enzyme which appears to possess multiple active sites that interact in a cooperative (negative) fashion in the presence of the inhibitor. MP was selective for the recombinant HIV-1 RT (p66) utilizing poly(rA) and oligo(dT)12-18 (4:1) as template-primer. Greater inhibition was observed with this template primer as compared with other natural and synthetic template-primers tested. MP had significantly less effect on avian myeloblastosis virus RT as well as mammalian or bacterial DNA and RNA polymerases. Other members of the ipecac class of alkaloids, e.g. emetine hydrochloride, were inactive against all of these enzymes, including HIV-1 RT. Conversely, MP did not inhibit in vitro protein synthesis, a property manifested by all the other ipecac alkaloids tested. Studies conducted with structural analogs revealed that the imine functionality at positions 1' and 2' of MP is the key structural requirement for HIV-1 RT inhibitory activity. Therefore, MP appears to possess unique structural properties that enable interaction with HIV-1 RT in a manner that can be differentiated from other polymerases. Use of these alkaloids for the definition of this viral enzyme-specific topology may lead to the development of therapeutically useful chemotherapeutic agents.

A review of the management of oral drug overdose in the Accident and Emergency Department of the Royal Brisbane Hospital.

Two-hundred and eighty-nine patients who made a total of 323 presentations to the Royal Brisbane Hospital Accident and Emergency Department with a known or suspected oral drug overdose were reviewed. The majority of patients (76%) could be managed in a 24 h Accident and Emergency observation unit. Activated charcoal given orally or via a nasogastric tube was the recommended method of preventing further absorption of an ingested drug. The use of syrup of ipecac was not encouraged and orogastric lavage was used in only specific situations. The morbidity and mortality of these patients when compared with other studies, was not adversely affected by this protocol which dramatically reduced the indications for the use of orogastric lavage and syrup of ipecac.

The responses of arginine vasopressin and adrenocorticotrophin to nausea induced by ipecacuanha.

Ipecacuanha syrup induces emesis by an early peripheral (gastric irritant) action and a later central effect at the chemoreceptor trigger zone (CTZ). We have studied the responses of plasma AVP, ACTH and ACTH-precursors to early and late ipecacuanha-induced nausea in nine healthy male subjects. Symptom severity was assessed using a linear analogue scale. All subjects reported 'early' nausea (N1) with a latency of 16 +/- 2 min (mean +/- SEM) and eight subjects vomited. Six subjects experienced recurrent nausea (N2) (latency 106 +/- 10.4 min) of whom five also vomited. The interval between the cessation of N1 and the onset of N2 was 55 +/- 10.8 min (range 25-80 min). The severity of nausea at the onset of N1 or N2 was similar but the AVP and ACTH responses were highly variable. Thus, while mean plasma AVP concentrations increased during both symptom periods, in three subjects during N1 and in three subjects during N2 plasma AVP concentrations did not rise above the normal range, despite marked symptoms. No clear pattern of AVP response to distinguish early peripheral from late central ipecacuanha-induced emesis was demonstrated. Whilst mean plasma ACTH concentrations increased during both N1 and N2 there were no changes in mean plasma ACTH-precursor concentrations. Analysis of pooled data for N1 and N2 demonstrated direct correlations between the nausea score and the peak incremental plasma responses of either AVP or ACTH and, despite the variability, peak incremental concentrations of AVP and of ACTH were also correlated. The data indicate that there is no difference in the AVP responses to peripherally or centrally stimulated ipecacuanha-induced nausea.(ABSTRACT TRUNCATED AT 250 WORDS)

Tubulosine: an antitumor constituent of Pogonopus speciosus.

From the antitumor-bioactive sap of Pogonopus speciosus, tubulosine [1] was isolated, by activity-directed fractionation using the brine shrimp lethality test, as the major antitumor constituent. 1H-nmr assignments, obtained from HETCOR and COSY, and X-ray crystallographic results are reported for the first time. Psychotrine [2] was also isolated, and its spectral data are also reported.

Drug-induced purposeless chewing: animal model of dyskinesia or nausea?

Drug-induced purposeless chewing movements in rodents are often considered to represent movement disorders or dyskinesias. We have compared the ability of drugs to induce chewing and retching or emesis in squirrel monkeys; such studies are not possible in rodents, which do not vomit. Acute administration of oxotremorine (3.3-33 micrograms/kg IM), SKF38393 (1-30 mg/kg SC) or ipecacuanha (0.5-0.75 mg/kg PO) caused dose-related increases in purposeless chewing which was frequently associated with retching and emesis. Treatment with haloperidol (0.015-0.06 mg/kg IM) did not induce chewing. Rather, haloperidol decreased spontaneous chewing at doses of 0.03 and 0.06 mg/kg. Our findings indicate that at least some drug-induced oral behaviours in rodents may reflect nausea rather than dyskinesia.