Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “SPARTEINE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed1986

A simple borohydride/GC method for measuring sparteine metabolites in man.

A simple borohydride/GC method was developed for phenotyping sparteine oxidation in man. The major metabolites of sparteine found in human urine, 2- and 5-dehydrosparteine, were converted quantitatively back to sparteine by sodium borohydride reduction. The amount of sparteine metabolites can be estimated from the difference of sparteine concentrations between the borohydride-treated and untreated urine samples. The coefficient of variation of this assay was estimated from repeated analyses to be +/- 3% within a day (intra-assay) and +/- 8% between days (inter-assay).

Borohydrides↗
PubMed1987

Evidence for polymorphic oxidation of sparteine in Japanese subjects.

The metabolism of sparteine which exhibits a genetic polymorphism in Caucasians was studied in 84 unrelated Japanese subjects. In contrast to a recent study where debrisoquine was used as a probe and no poor metabolizers could be observed in Japanese involving 100 subjects, two subjects had a urinary metabolic ratio of sparteine greater than 20 and thus were poor metabolizers of sparteine. The incidence of poor metabolizer phenotype of sparteine oxidation of 2% seems to be lower in Japanese as compared with various Caucasian populations where 5 to 10% are poor metabolizers of sparteine. However, this is not conclusive, because the 95% confidence interval of the observed frequency, 0.6 to 8%, covers the range reported in the literature for Caucasians.

Adult↗
PubMed1989

Substantial rise in sparteine metabolic ratio during haloperidol treatment.

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1-2 times during oral haloperidol treatment in doses of 10-40 mg day-1. In patients classified as extensive metabolisers (sparteine MR less than 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum-haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60-80 nM) an increase in sparteine MR by a factor 15-50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day-1 was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22-1.47).

Adult↗
PubMed1982

[Experimental studies on therapeutic modification of sparteine poisoning].

We investigated the influence of an intoxication with sparteine (10 mg/kg X min i.v.) on heart rate, arterial blood pressure, cardiac output, stroke volume and total peripheral resistance in anesthetized rats. The leading feature of the cardiovascular activity of sparteine in rats was a strong bradycardia whereas blood pressure, cardiac output and peripheral resistance only slightly decreased and stroke volume even increased. The death of the rats occurred with a sudden stop of the QRS complexes in the ECG and an abrupt fall of blood pressure. Isoprenaline, orciprenaline, dopamine and prenalterol were compared with respect to their efficacy in reversing sparteine-induced toxicity in rats. Prenalterol proved to be the best antidote on account of its specific action on adrenergic beta 1-receptors. This result was affirmed in two experiments in pigs. Isoprenaline may also be used as an antidote for sparteine but decreases the blood pressure. Vasoconstrictors like dopamine should only be used in sparteine intoxication when a severe fall of blood pressure occurs which can not be overcome by prenalterol or isoprenaline.

Anesthesia↗
PubMed1989

Polymorphic sparteine metabolism and amyotrophic lateral sclerosis.

The activity of detoxication with the cytochrome P450 family of enzymes was studied in patients with amyotrophic lateral sclerosis (ALS). The metabolic ratio (MR) of sparteine sulphate was measured, and the population of phenotypes for sparteine nitro (N)-oxidation was determined in 30 patients with ALS and 41 controls for the assay of the sparteine N-oxidation by the cytochrome P450 enzymes. A lower MR and higher frequency of efficient metabolizers were observed in the ALS group, suggesting that there is efficient sparteine N-oxidation by cytochrome P450 pathways in ALS. This tendency was more marked in 15 patients with ALS aged under 60 years.

Adult↗
PubMed1979

Defective N-oxidation of sparteine in man: a new pharmacogenetic defect.

Sparteine, an antiarrhythmic and oxytocic drug, is metabolised by N1-oxidation. The sparteine-N1-oxide rearranges with loss of water to 2- and 5-dehydrosparteine. 18 (i.e., 5%) out of 360 subjects were unable to metabolise the drug. These persons, who were designated as nonmetabolisers, excreted almost 100% of the administered dose in urine as unchanged drug. The defective metabolism of sparteine was found to have a genetic basis. Sparteine-N1-oxidation appears to be determined by two allelic genes at a single locus where nonmetabolisers are homozygous for an autosomal recessive gene.

Family↗
PubMed1987

Effect of sparteine sulphate upon basal and nutrient-induced insulin and glucagon secretion in normal man.

Infusion of a therapeutic dose of sparteine sulphate, increased the basal plasma insulin level and lowered plasma glucose. When an intravenous glucose tolerance test was performed with the infusion, the total insulin AUC was significantly larger than in absence of sparteine (2025 vs 1464 microU/ml X min), plasma glucose levels were lower and improved glucose utilization was observed (kg:1.55 vs 1.39%). In the presence of arginine, sparteine sulphate stimulated both beta and alpha cells, increasing both the total insulin (1907 vs 1516 microU/ml X min p less than 0.02) and total glucagon AUCs (7616 +/- 654 vs 6789 +/- 707 pg/ml X min p less than 0.01). Thus, sparteine sulphate increased both basal and nutrient-induced insulin and glucagon secretion in normal man.

Adult↗
PubMed1998

Codeine in post-operative pain. Study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide.

OBJECTIVE: Within the past decade, human experimental pain studies have supported the 50-year-old hypothesis that codeine is a prodrug, which has to be converted to morphine to exert an analgesic effect. This study aimed at evaluating the impact of sparteine phenotype and serum concentrations of morphine on the efficacy of codeine in post-operative pain. METHODS: Eighty-one patients with a pain rating of 3 or more on a 0-10 numerical rating scale 0.5 h after surgery were included in the study. The patients were given an oral dose of 100 mg codeine and rated pain with the numerical rating scale 0.5 h and 1 h after medication. Blood for determination of serum concentration of codeine and its metabolites was collected 1 h after medication, and a 12-h urine sample after administration of 100 mg sparteine was used to determine the sparteine phenotype. RESULTS: Eight patients were poor metabolizers and 66 were extensive metabolizers of sparteine, while the urine samples for the remaining seven patients were lost. In 22 patients, including the eight poor metabolizers, the serum concentrations of both morphine and morphine-6-glucuronide (M6G) were below the limit of determination of the assay, i.e. 1.5 nmol x l(-1) and 2 nmol x l(-1), respectively. A sum of the concentration of these two substances below 10 nmol x l(-1) was found in an additional eight patients. The sum of differences between pre- and post-operative pain ratings did not differ between the two phenotypes (P = 0.60), whereas the 30 patients with serum concentrations of morphine plus M6G below 10 nmol x l(-1) had a marginally significant lower sum than the 51 patients with higher levels of these substances (median 1.5 vs 2.5, P = 0.058). CONCLUSION: A low serum concentration of morphine and M6G seems to be common in patients treated with codeine for post-operative pain, and low concentrations of these active substances may be related to decreased efficacy of codeine.

Adult↗
PubMed1983

Inhibition of sparteine oxidation in human liver by tricyclic antidepressants and other drugs.

Testing for competitive inhibition of sparteine oxidation in the 9000 x g supernatant fraction from human liver provides an in vitro means to identify drugs which can bind to the same form of cytochrome P450 which oxidizes sparteine. There has so far been only two outcomes of this test: either the drug examined competed with sparteine for a common binding site, or it did not inhibit the reaction. The results of such in vitro testing implicated the involvement of guanoxan, nortriptyline, desipramine, imipramine, amitriptyline and chlorpromazine with this enzyme. Amobarbital, tolbutamide and guanethidine in therapeutic concentrations did not interfere with sparteine oxidation by this preparation.

Antidepressive Agents, Tricyclic↗
PubMed1986

A sensitive capillary GC assay for the determination of sparteine oxidation products in microsomal fractions of human liver.

A sensitive method for the assay of sparteine oxidase activity in vitro by microsomal fractions of human liver is described. The activity of sparteine oxidase was assessed by the formation of 2- and 5-dehydrosparteines, which were estimated by capillary gas chromatography with N2-FID detection. The limit of detection of the two metabolites, 2- and 5-dehydrosparteine, was 10 pmol (2.3 ng) per sample. Sparteine oxidase activity was linear with microsomal protein concentration ranging from 25 to 200 ug and with incubation times between 5 and 60 minutes. Omission of NADPH on incubation under an atmosphere of carbon monoxide inhibited formation of both metabolites, thus indicating that aforementioned metabolites arise in reaction catalyzed by cytochrome P-450. In three liver samples from humans classified as extensive (EM) metabolizers the formation of 2- and 5-dehydrosparteines was observed, 2-dehydrosparteine being the major metabolite. In these samples sparteine oxidase activity was characterised by Vmax = 136 +/- 53 pmol/min/mg and Km = 44 +/- 12 microM for 2-dehydrosparteine formation. For 5-dehydrosparteine formation the following values were obtained: Vmax = 57 +/- 18 pmol/min/mg and Km = 42 +/- 26 microM. In a liver sample from a poor metabolizer (PM) only the formation of 2-dehydrosparteine was detected with the method of analysis used. In this sample a great increase in Km (Km PM = 3033 microM) was noted, while Vmax was very similar to those obtained for 2-dehydrosparteine formation in EM subjects (Vmax PM = 147 pmol min/mg).

Chromatography, Gas↗
PubMed2004

Evaluation of (+)-sparteine-like diamines for asymmetric synthesis.

Three new (+)-sparteine-like diamines were prepared from (-)-cytisine and evaluated as sparteine surrogates in the alpha-lithiation rearrangement of cyclooctene oxide and the palladium(II)/diamine catalyzed oxidative kinetic resolution of 1-indanol. The new diamines exhibited opposite enantioselectivity to that observed with (-)-sparteine but increasing the steric hindrance of the N-alkyl group beyond N-Et had a detrimental effect on enantioselectivity. The optimal N-Me diamine was evaluated with much success in five other (-)-sparteine-mediated processes involving different metals (lithium, magnesium, and copper) and different types of reaction mechanisms.

Alkaloids↗
PubMed1983

Comparative pharmacogenetics of sparteine and debrisoquine.

Capacities to oxidize sparteine and debrisoquine in healthy Canadian Caucasians were compared. The Spearman rank correlation between the conventional urinary metabolic ratios (drug/metabolite) was rs = 0.79 (P less than 0.001), but the sparteine metabolic ratio appears to be the more discriminating probe to distinguish metabolizers and nonmetabolizers. The urinary amount of oxidized sparteine alone may allow reliable detection of nonmetabolizers. From a total of 17 poor metabolizers observed in this study and in studies in Germany and Sweden, all were deficient in metabolizing capacity for both sparteine and debrisoquine.

Chromatography, Gas↗
PubMed1986

Sparteine oxidation polymorphism in Greenlanders living in Denmark.

Sparteine oxidation appeared to be polymorphic in 185 healthy Greenlanders living in Denmark. Six subjects (3.2%) were phenotyped as poor metabolizers (PM) and 179 subjects as extensive metabolizers (EM). The metabolic ratio (MR) between sparteine and 2- + 5-dehydrosparteine in a 12 h urine sample ranged from 0.06-3.12 in EM and from 30-480 in PM. The excretion of dehydrosparteines accounted for less than 2.2% of the dose in PM and ranged from 5.6%-63% in EM. The urinary recovery (% of dose) of sparteine, 2-dehydrosparteine and total sparteine + dehydrosparteines was lower in Greenlander EM than in Danish EM (Brøsen et al., 1985). Incomplete urine collection in a substantial proportion of the Greenlanders could explain these discrepancies.

Adolescent↗
PubMed1990

Sparteine metabolism capacity in human liver: structural variants of human P450IID6 as assessed by immunochemistry.

An antibody raised against rat P450dbl was used to examine the heterogeneity of the human enzyme involved in the sparteine/debrisoquine polymorphism. The extent to which the antibody was able to inhibit sparteine metabolism varied in different human livers (10-80%, n = 9) and reflected the amount of sparteine metabolism carried out by the polymorphic P450IID6 in individual liver specimens. The individual sample variation in inhibition by the antibody correlated with the inhibition caused by quinidine, a prototype competitive inhibitor of the P450IID6 enzyme active site. Western immunoblots of the liver microsomes confirmed that the variation in the inhibition of sparteine metabolism by this antibody reflected the amount of P450IID6 protein. In addition, a detailed study of one of the livers (K19) which demonstrated a lack of inhibition by the antibody was performed which confirmed the lack of P450IID6 in this liver specimen and suggested that the nascent sparteine metabolism activity was due to other forms of P450.

Animals↗
PubMed1998

A comparative study of the effects of sparteine, lupanine and lupin extract on the central nervous system of the mouse.

Lupin is toxic because of its alkaloid content, sparteine and lupanine in particular. Although the pharmacological properties of sparteine are well known those of lupanine have not been much studied. This paper reports procedures for extraction, purification and crystallization of lupanine, and methods for the preparation of an extract for injection of Lupinus mutabilis Sweet, and for the determination of the acute toxicity and maximum non-lethal dose (DL0) of lupanine, sparteine and lupin extract in the mouse. The three substances were tested on the central nervous system (CNS) for locomotor activity, for interaction with specific drugs used for treatment of the CNS (the stimulant drugs amphetamine and pentetrazol and the depressant drugs pentobarbital and chlorpromazine) and for analgesic activity. The results indicate that lupanine and lupin extract are less toxic than sparteine and that at the doses studied the three products have a weak sedative effect on the CNS.

Alkaloids↗
PubMed1986

The genetic polymorphism of sparteine metabolism.

The formation of the two major metabolites of the antiarrhythmic and oxytocic drug sparteine (2- and 5-dehydrosparteine) exhibits a genetic polymorphism. Two phenotypes, extensive (EM) and poor metabolizers (PM) are observed in the population. The frequency of the PM phenotype in various populations (Caucasian and Japanese) ranges from 2.3 to 9%. The metabolism of sparteine is determined by two allelic genes at a single gene locus. PM subjects are homozygous for an autosomal recessive gene. The metabolism of sparteine is predominantly under genetic control as treatment with drugs such as antipyrine and rifampicin known to induce oxidative drug metabolism elicited only marginal changes in sparteine metabolism. The formation of 2-dehydrosparteine in human liver microsomes from EM and PM subjects showed a more than 40-fold difference in Km between EM and PM subjects. However, Vmax-values were almost identical in both groups. These data indicate that the basis of the differences in oxidative capacity between EM and PM subjects is more likely to be due to a variant isozyme with defective catalytic properties than to a decreased amount of the isozyme.

Animals↗
PubMed1991

Regioselectivity and stereoselectivity of the metabolism of the chiral quinolizidine alkaloids sparteine and pachycarpine in the rat.

1. The metabolism of (-)-sparteine and (+)-sparteine (pachycarpine) was investigated in male Sprague-Dawley rats by g.l.c.-mass spectrometry, and 13C- and 2H-n.m.r. spectroscopy. The structure of the major metabolite of (-)-sparteine was confirmed to be 2,3-didehydrosparteine by g.l.c.-mass spectrometry after alkaline sample work-up. 2H-n.m.r. spectroscopy showed that this metabolite exhibits the structure of the carbinolamine (2S)-hydroxysparteine in aqueous solution of neutral pH. No other metabolites with an enamine structure were observed by g.l.c.-mass spectrometry and 13C-n.m.r. spectroscopy. 2. Pachycarpine is metabolized in vivo and in vitro stereoselectively to the aliphatic alcohol (4S)-hydroxypachycarpine as the main metabolite. 3. The formation of the 2,3-didehydrosparteine proceeds via stereospecific abstraction of the axial 2 beta hydrogen atom. Inhibition in vitro studied with purified rat liver microsomes demonstrated that both sparteine enantiomers are metabolized by the same cytochrome P450 isozyme. Therefore this enzyme exhibits marked substrate and product stereoselectivity for the metabolism of the two enantiomeric quinolizidine alkaloids.

Administration, Oral↗
PubMedDate not supplied

A nuclear magnetic resonance study of sparteine delta metabolite structure.

Originally, the enamines 2,3- and 5,6-didehydrosparteine (2a and 3a, respectively) had been characterized by GC/MS as metabolites after administration of (-)-sparteine sulfate (1a.H2SO4). Since the existence of free enamines in aqueous medium seemed rather doubtful, the metabolism of (-)-sparteine was reinvestigated by high-resolution 1H-, 2H-, and 13C-NMR spectroscopy. When synthetic 1,2-didehydrosparteinium monoperchlorate (4a.ClO4) is dissolved in aqueous medium at pH 4-9, sterically uniform (2S)-hydroxysparteine (6a) is formed, as is proven unequivocally by 1H- and 13C-NMR. However, at pH less than or equal to 2, this carbinolamine eliminates water under reconstitution of the iminium structure 4a. No carbinolamine is formed, in contrast, from synthetic 1,6-didehydrosparteinium monoperchlorate (5a.ClO4). Upon oral application of [2R-2H]sparteine (1b), as the sulfate, the respective carbinolamine and iminium structures 6b and 5b are identified in the urines by 2H-NMR spectroscopy. Reversed-phase TLC likewise confirms the different structural principle of the two main sparteine metabolites. The free enamine bases, characterized by GC/MS, thus must be regarded as artifacts, formed in the work-up requisite for GC analysis.

Chromatography, Thin Layer↗