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At least 19 recordsLinked to original sources
PubMed1986

Comparative bioavailability and pharmacokinetics of noscapine hydrogen embonate and noscapine hydrochloride.

The relative bioavailability and pharmacokinetics of two orally administered aqueous suspensions of noscapine hydrogen embonate were compared with those of noscapine hydrochloride solution. Noscapine hydrochloride showed faster absorption and gave a higher peak concentration than the embonate. The average bioavailability of the embonates was 71% of that of the noscapine solution (p less than 0.05). No significant difference was observed when the embonate was administered with water, polyvidone and flavouring agents.

Adult↗
PubMed2000

Noscapine inhibits tumor growth with little toxicity to normal tissues or inhibition of immune responses.

Noscapine, a phthalideisoquinoline alkaloid derived from opium, has been used as an oral anti-tussive agent and has shown very few toxic effects in animals or humans. Recently, we reported that noscapine binds stoichiometrically to tubulin and promotes microtubule polymerization. Noscapine causes growth arrest of tumor cells in mitosis and induces apoptosis of tumor cells in vitro. Previous experiments also showed that noscapine has potent antitumor activity in mice when administered parenterally or by gastric lavage. Here, we report that the anti-mitotic effect was specific to noscapine since closely related compounds did not inhibit the growth of a lymphoma cell line. In addition, noscapine was shown to be effective in reducing the growth of the lymphoma and increasing the survival of tumor-bearing mice when administered in the drinking water. It is noteworthy that, noscapine showed little or no toxicity to kidney, liver, heart, bone marrow, spleen or small intestine at tumor-suppressive doses. Furthermore, oral noscapine did not inhibit primary immune responses, which are critically dependent upon proliferation of lymphoid cells. Thus, our results indicate that noscapine has the potential to be an effective chemotherapeutic agent for the treatment of human cancer.

Alkaloids↗
PubMed1999

Noscapine hydrochloride disrupts the mitotic spindle in mammalian cells and induces aneuploidy as well as polyploidy in cultured human lymphocytes.

Noscapine hydrochloride is a centrally acting antitussive opium derivative widely used in cough suppressants. Recent studies have reported that noscapine is a potent inducer of polyploidy but not of aneuploidy in vitro. To obtain more comprehensive information about the cytogenetic effects of this compound, we treated cultured human lymphocytes (HPL) and Chinese hamster ovary (CHO) cells with various concentrations of noscapine hydrochloride. Using a differential staining technique noscapine was shown to disrupt the mitotic spindle at concentrations < 5 micrograms/ml in both cell types. The use of multicolor fluorescence in situ hybridization (FISH) on noscapine-treated human lymphocytes showed a dose-dependent induction of hyperdiploidy of chromosome 1 but not of chromosomal breakage in the 1cen-q12 region under in vitro conditions, indicating that noscapine is specifically inducing numerical chromosomal aberrations. FISH with probes targeting different chromosomes revealed that noscapine is capable of inducing both polyploidy and true hyperdiploidy. Our results show that noscapine, by disrupting the function of the mitotic spindle, has the ability to induce aneuploidy and not uniquely polyploidy as previously reported. By using these types of molecular cytogenetic techniques, it should be possible to evaluate the ability of noscapine to induce aneuploidy in the upper intestinal tract in vivo.

Aneuploidy↗
PubMed2002

Noscapine alters microtubule dynamics in living cells and inhibits the progression of melanoma.

Cellular microtubules, polymers of tubulin, alternate relentlessly between phases of growth and shortening. We now show that noscapine, a tubulin-binding agent, increases the time that cellular microtubules spend idle in a paused state. As a result, most mammalian cell types observed arrest in mitosis in the presence of noscapine. We demonstrate that noscapine-treated murine melanoma B16LS9 cells do not arrest in mitosis but rather become polyploid followed by cell death, whereas primary melanocytes reversibly arrest in mitosis and resume a normal cell cycle after noscapine removal. Furthermore, in a syngeneic murine model of established s.c. melanoma, noscapine treatment resulted in an 85% inhibition of tumor volume on day 17 when delivered by gavage compared with untreated animals (P <or= 0.01), without evidence of toxicity to the spleen, liver, duodenum, bone marrow, or peripheral blood. This inhibition was greater than that seen in vivo by paclitaxel (Taxol) alone and similar to the inhibition of tumor volume observed when noscapine was combined with paclitaxel. Importantly, noscapine also demonstrated the ability to significantly inhibit melanoma progression by 83% on day 18 when delivered in drinking water (P <or= 0.01) and conferred a significant survival advantage (P <or= 0.01). Our results demonstrate that p.o.-administered noscapine significantly inhibits the progression of melanoma cells through alterations in microtubule dynamics, with no detected toxicity to the host. Consequently, noscapine could be a valuable chemotherapeutic agent, alone or in combination, for the treatment of advanced melanoma.

Administration, Oral↗
PubMed2003

Brominated derivatives of noscapine are potent microtubule-interfering agents that perturb mitosis and inhibit cell proliferation.

Noscapine, a microtubule-interfering agent, has been shown to arrest mitosis, to induce apoptosis, and to have potent antitumor activity. We report herein that two brominated derivatives of noscapine, 5-bromonoscapine (5-Br-nosc) and reduced 5-bromonoscapine (Rd 5-Br-nosc), have higher tubulin binding activity than noscapine and affect tubulin polymerization differently from noscapine. In addition, they are able to arrest cell cycle progression at mitosis at concentrations much lower than noscapine. Interestingly, whereas noscapine-arrested cells have nearly normal bipolar spindles, cells arrested by 5-Br-nosc and Rd 5-Br-nosc form multipolar spindles. Nevertheless, noscapine and the two derivatives all affect the attachment of chromosomes to spindle microtubules and they impair the tension across paired kinetochores to similar degrees. 5-Br-nosc and Rd 5-Br-nosc are also more active than noscapine in inhibiting the proliferation of various human cancer cells, including those that are resistant to paclitaxel and epothilone. Our results thus indicate a great potential for the use of 5-Br-nosc and Rd 5-Br-nosc both as biological tools for studying microtubule-mediated processes and as chemotherapeutic agents for the treatment of human cancers.

Antitussive Agents↗
PubMed1990

Pharmacokinetics of oral noscapine.

The relative bioavailability in 20 healthy volunteers of 100 mg, 200 mg and 300 mg tablets of noscapine and 200 mg as a solution has been assessed in a four-way cross-over study, with repeated administration of the 200 mg dose to assess intraindividual variability. There was a disproportionate increase in the AUC of noscapine tablets, as a 3-fold increase in dose produced a 9-fold rise in AUC. This dose-dependency could mainly be attributed to saturable first-pass metabolism of the drug. Administration of noscapine as a solution resulted in a significantly higher maximal concentration at an earlier time-point and a higher AUC than the corresponding dose as tablets. Repeated administration of noscapine tablets and solution yielded higher AUC on the second dosing occasion. No cause for this carry-over effect was found, and the contribution of remaining noscapine was negligible. The terminal half-life of noscapine, which was independent of formulation or dose size was 4.5 h. Both inter- and intraindividual variability in noscapine kinetics were very high, e.g. 73% and 51% CV of the AUC for the 200 mg tablet.

Administration, Oral↗
PubMed1993

Noscapine does not show aneugenic activity in mouse oocytes.

To clarify if noscapine has the ability to induce polyploidy in rodent germ cells in vivo, a cytogenetic study of mouse metaphase II oocytes was conducted after oral treatment with noscapine at the doses of 20, 120 and 400 mg/kg. Plasma concentrations of noscapine were measured by reversed-phase liquid chromatography and UV detection in three satellite groups of mice up to 8 h after administration of these doses. Thus, the relationship of the maximum plasma concentration and the area under the curve (AUC) with that of meiotic progression could be established. Although noscapine was tested at the maximum tolerated dose, no delay of meiotic progression or induction of chromosome malsegregation could be shown as no increase in the frequency of metaphase I-arrested, polyploid or hyperploid oocytes were found. At the highest dose only, noscapine affected the physiology of superovulation as shown by a significant decrease in the mean number of oocytes harvested per female. In view of the large span covered by the doses tested, corresponding to concentrations far above those detected in humans, and the similarity between the pharmacokinetics of noscapine in mouse and humans, it is unlikely that noscapine represents a genetic risk for humans at therapeutic dosages.

Aneuploidy↗
PubMed2003

Interaction of noscapine with the bradykinin mediation of the cough response.

Angiotensin Converting Enzyme Inhibitors (ACEI) like captopril and enalapril, can induce persistant cough in man. Noscapine, an antitussive alkaloid, can be used to suppress ACEI-induced cough. Some workers have suggested a role for bradykinin in precipitation of ACE-induced cough. Work carried out in our laboratory has shown noscapine to be a non-competitive inhibitor of bradykinin in guinea pig ileum. It is therefore possible that noscapine suppresses cough by blocking the effect of bradykinin receptor activation in the airways. Guinea pigs were placed in a cough-chamber connected to an air pump and a pressure transducer. Capsaicin was sprayed into the chamber and cough was recorded as a distinctive change in air pressure inside the cough-chamber. Animals treated with 1 mg/kg captopril and enalapril for 7 days, showed increased cough response. Ten microgram/kg FR190997, a non-peptide agonist of the bradykinin B2 receptor, also increased the cough response. Noscapine at 0.5, 1 and 2 mg/kg was able to reverse the effects of ACEI and FR190997. Naloxone, a specific opioid receptor inhibitor, did not block the antitussive effects of noscapine in enalapril or FR190997 treated guinea pigs. This antitussive effect of noscapine is not mediated via the mu, kappa or delta opioid receptors. It is therefore possible that noscapine exerts its antitussive action by interfering with the bradykinin cough mediation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Noscapine and analogues as potential chemotherapeutic agents.

Noscapine, an antitussive drug, has been previously shown to inhibit the growth of cultured tumor cells and tumors implanted in nude mice. Like some other antitumor agents, noscapine targets a cellular protein, tubulin, that is responsible for the assembly of important scaffolding polymers, microtubules. As a result, noscapine causes the aberrant assembly of the cellular machinery necessary for cell division, the mitotic spindle. This is followed by apoptotic cell death. Current evidence suggests that the antitumor activity of noscapine might lie in its initiation of apoptotic pathways. Compared with other microtubule drugs, noscapine has low toxicity and wide efficacy in animal models. For clinical use, noscapine affords simple means of administration including oral, rectal, parenteral or by simple inhalation of suitable aerosols. Thus, noscapine and its analogues are potential cost-effective chemotherapeutic agents for the treatment of human cancers.

Journal Article↗
PubMed1988

Characterization of high-affinity binding sites for the antitussive [3H]noscapine in guinea pig brain tissue.

We have characterized the binding of the antitussive alkaloid [3H]L-alpha-noscapine ([3H]noscapine) to guinea pig brain. Binding of [3H]noscapine to brain homogenate is stereospecific, saturable, reversible, heat-sensitive and manifests high affinity (Kd = 7 nM). Binding sites are present in all major brain areas, with the thalamus exhibiting the highest density. Subcellular localization studies showed an enrichment of binding sites in the synaptosomal fraction. Some structurally related compounds with antitussive properties (narceine, hydrastine, narcotoline and papaverine) were potent competitors, while other antitussives did not inhibit [3H]noscapine binding. Various ligands that bind to known neurotransmitter receptors failed to displace [3H]noscapine binding or had IC50 values in the micromolar range. It was concluded that the noscapine binding sites are different from those previously described for antitussives such as codeine and other opiates, or dextromethorphan.

Animals↗
PubMed1991

Noscapine-induced polyploidy in vitro.

The conditions under which noscapine causes high levels of polyploidy in vitro in human lymphocytes were investigated to try to determine its mode of action and to assess whether it was likely to be a genotoxic hazard when used as an antitussive agent. Irrespective of duration of treatment or type of medium, there seemed to be a threshold for polyploidy induction between 15.0 and 30.0 micrograms/ml and a maximum between 100.0 and 150.0 micrograms/ml noscapine. High levels (10.0-20.0%) of noscapine-induced polyploidy were never found with 4 h treatments or with RPMI 1640 medium plus 15% (v/v) foetal calf serum; the use of Iscove's modified Dulbecco's medium and 24 h treatments were needed. The reasons for these observations seemed to be the faster cell division and greater sensitivity of cells grown in Iscove's medium. There was conflicting evidence about the mechanism of polyploidy induction by noscapine; either spindle damage or cell fusion remain as possibilities. The need for prolonged exposure and the precise nutritional requirements suggest that a short exposure, albeit at high concentration, in the upper gastro-intestinal tract is unlikely to be a hazard for humans. Furthermore, evidence of a threshold at approximately 20 micrograms/ml plus the virtual elimination of noscapine-induced polyploidy by microsomal metabolism (S9 mix) together with published metabolic data imply that the low-level systemic exposure after absorption may well not be hazardous. We conclude that the use of noscapine in cough mixtures does not pose a significant potential hazard for humans.

Bromodeoxyuridine↗
PubMed1990

Serum protein binding of noscapine: influence of a reversible hydrolysis.

The binding of the antitussive drug noscapine to human serum, pure albumin and alpha 1-acid glycoprotein has been investigated by ultrafiltration and equilibrium dialysis, using radiolabelled noscapine. The binding in serum pooled from volunteers was 93 +/- 0.2% (at 100 ng mL-1). After incubation for 24 h the binding decreased to about 85% (ultrafiltration 87.0 +/- 1.0%; equilibrium dialysis 84.3 +/- 1.2%), because of the conversion of noscapine to noscapinic acid. Only unbound drug underwent this hydrolysis, and as noscapine is extensively bound in healthy volunteers, this elimination process is probably unimportant. The major binding protein of noscapine was albumin (K = 3060 M-1, n = 5.62), but the binding to alpha 1-acid glycoprotein was also substantial (K = 31,500 M-1, n = 1.73). The interindividual variation in binding was low and binding was linear at the concentrations observed after therapeutic doses (0-500 ng mL-1).

Blood Proteins↗
PubMed1992

[3H]noscapine binding sites in brain: relationship to indoleamines and the phosphoinositide and adenylyl cyclase messenger systems.

High affinity [3H]noscapine binding sites are brain specific, ion insensitive, and present in a variety of species and show strict structure-activity requirements. Among neurotransmitter-related structures, indoleamines and beta-carbolines display highest affinity for [3H]noscapine sites. Noscapine inhibits carbachol-stimulated phosphoinositide turnover in guinea pig and rat brain slices, with structural analogs possessing similar relative potencies for binding to [3H]noscapine binding sites and inhibiting phosphoinositide turnover. Noscapine and its derivatives also markedly enhance the ability of forskolin to augment cAMP levels in brain slices, with relative potencies paralleling affinities for noscapine binding sites.

Adenylyl Cyclases↗
PubMed2002

Paclitaxel-resistant human ovarian cancer cells undergo c-Jun NH2-terminal kinase-mediated apoptosis in response to noscapine.

We have previously discovered the opium alkaloid noscapine as a microtubule interacting agent that binds to tubulin, alters the dynamics of microtubule assembly, and arrests mammalian cells at mitosis (Ye, K., Ke, Y., Keshava, N., Shanks, J., Kapp, J. A., Tekmal, R. R., Petros, J., and Joshi, H. C. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 1601-1606; Ye, K., Zhou, J., Landen, J. W., Bradbury, E. M., and Joshi, H. C. (2001) J. Biol. Chem. 276, 46697-46700; Zhou, J., Panda, D., Landen, J. W., Wilson, L., and Joshi, H. C. (2002) J. Biol. Chem. 277, 17200-17208). Here we show that noscapine does not compete with paclitaxel for tubulin binding and can efficiently inhibit the proliferation of both paclitaxel-sensitive and paclitaxel-resistant human ovarian carcinoma cells (i.e. the parental cell line 1A9 and two derivative cell lines, 1A9PTX10 and 1A9PTX22, which harbor beta-tubulin mutations that impair paclitaxel-tubulin interaction (Giannakakou, P., Sackett, D. L., Kang, Y. K., Zhan, Z., Buters, J. T., Fojo, T., and Poruchynsky, M. S. (1997) J. Biol. Chem. 272, 17118-17125). Strikingly, these cells undergo apoptotic death upon noscapine treatment, accompanied by activation of the c-Jun NH(2)-terminal kinases (JNK). Furthermore, inhibition of JNK activity by treatment with antisense oligonucleotide or transfection with dominant-negative JNK blocks noscapine-induced apoptosis. These findings thus indicate a great potential for noscapine in the treatment of paclitaxel-resistant human cancers. In addition, our results suggest that the JNK pathway plays an essential role in microtubule inhibitor-induced apoptosis.

Alleles↗
PubMed2001

Efffect of noscapine, the antitussive opioid alkaloid, on bradykinin-induced smooth muscle contraction in the isolated ileum of the guinea-pig.

Bradykinin (BK) and related kinins are autocoid peptides that play integral roles in many pathophysiological processes such as cough. In this study, the inhibitory effect of noscapine, the antitussive opioid alkaloid, on BK receptors, was tested in the guinea-pig ileum. Contractions of the isolated ileum of the guinea-pig in response to BK were inhibited by noscapine (10-1,000 nM) in a concentration-dependent manner. Concentration-response curves (CRCs) to BK were slightly shifted to the right with a concomitant decrease in the maximum effect. A pA2 value of 6.68 was calculated for noscapine. The slope of the Schild plot of the antagonism was found to be 0.56. Noscapine had no effect on contractions induced by KCl, acetylcholine, histamine, 5-hydroxy tryptamine or angiotensin II. In conclusion, noscapine has a specific antagonistic effect on BK receptors and the mode of inhibition was found to be non-competitive.

Animals↗
PubMed1992

Relative bioavailability in man of noscapine administered in lozenges and mixture.

The bioavailability of noscapine base administered in lozenges in a dose of 100 mg to twelve healthy volunteers, in a study using an open balanced cross-over design, was compared with that of 100 mg of noscapine hydrochloride given perorally as a mixture. The bioavailability of noscapine after administration in lozenges was significantly higher than that after administration of the drug as a mixture. It is concluded that the lozenges containing noscapine base may be a valuable alternative to the conventional noscapine hydrochloride mixture.

Adult↗
PubMed1991

Chewing gum and lozenges as delivery systems for noscapine.

Chewing gum and lozenges were evaluated as delivery systems for noscapine with the aim of developing improved antitussive preparations. The formulations studied were prepared with both the water-soluble hydrochloride salt of noscapine and with the poorly soluble embonate salt and noscapine free base. The release characteristics of the preparations were evaluated both in vitro and in vivo, and their taste properties examined. Only the formulations containing noscapine base were without any appreciable taste. Chewing gum containing this compound showed, however, a low level of drug release both in vitro and in vivo and is therefore not a suitable dosage form. Only a lozenge formulation containing noscapine base fulfilled the requirements of taste acceptability and adequate release properties.

Chewing Gum↗