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PubMed1986

Cardiovascular effect of sparteine in anaesthetized dogs with and without blockade of cardiac autonomic nerves.

L-Sparteine sulfate (sparteine, 3 mg/kg) was injected intravenously over 3 min in 12 anaesthetized dogs in order to evaluate the inotropic effect of this antiarrhythmic drug on the heart in intact organisms. There was a discrete decline in left ventricular dP/dtmax which was transient within 9 min. No influence could be detected on right ventricular pressure rise velocity. Aortic pressure increased by about 15% and a parallel increase in left ventricular enddiastolic pressure was observed. Heart rate was slightly diminished. Pharmacological blockade of cardiac autonomic nerves did not influence considerably the effect of sparteine. Pretreatment with captopril and phentolamine did not abolish the vasoconstrictive property which was also present in a reserpine pretreated dog. Sparteine shows no pronounced inotropic effect in the heart in situ. It increases arterial blood pressure by direct vascular constriction.

Adrenergic alpha-Antagonists↗
PubMed1975

[Effect of sparteine sulfate on the predamaged conduction system of the heart].

Antiarrhythmic drugs are known to cause AV-blockade. In animals and healthy humans the alcaloid of the gorse sparteine sulphate has been reported not to cause those side effects. We have studied in 10 patients with predamaged conduction system the grade of AV-blockade, the AV-interval and the intraventricular excitation spread by e.c.g. after i.v. injection of 200 mg sparteine sulphate (ajmalin, 50 mg i.v. as control). In 6 out of 10 patients no side effects have been observed. In 4 patients both sparteine and ajmalin injection caused higher graded AV-blockade. Our results suggest that sparteine sulphate like other antiarrhythmic drugs should not be administered to patients with a predamaged conduction system.

Ajmaline↗
PubMed1976

Aminopyridines and sparteine as inhibitors of membrane potassium conductance: effects on Myxicola giant axons and the lobster neuromuscular junction.

The effects of the compounds 2-, 3- and 4-aminopyridine and sparteine on membrane conductance changes were examined using both voltage-clamped Myxicola axons and the lobster neuromuscular junction. In Myxicola axons, the aminopyridines very specifically inhibited the potassium conductance when applied at concentrations of 0.1 mM to 5 mM without any apparent effect of resting membrane potential. Concentrations in excess of 5 mM were needed to inhibit noticeably the sodium conductance. Potassium conductance-voltage curves were shifted in the depolarized direction along the voltage axis with no significant change in shape. There were only minor changes in the kinetics of potassium activation. In high potassium solutions, both inward and outward potassium currents were equally sensitive to the aminopyridines. Sparteine was, in general, found to be a more potent, but somewhat less specific, inhibitor of the potassium conductance. In contrast to the aminopyridines, sparteine was more effective when applied at basic pH and in addition tended to produce a noticeable degree of potassium inactivation. When applied to the lobster neuromuscular junction, 2-aminopyridine and sparteine dramatically increased the amplitude of both excitatory and inhibitory postjunctional potentials, with little or no change in resting potential, resting input conductance, reversal potential, or miniature end plate potential amplitude or frequency. Quantal content per fiber was increased by approximately a factor of 3 for the excitatory responses.

Animals↗
PubMed1988

Plasma glucose lowering effect of sparteine sulphate infusion in non-insulin dependent (type 2) diabetic subjects.

Sparteine sulphate, given i.v. as a bolus of 15 mg/ml plus 90 mg in 0.9% NaCl 100 ml over 60 min, increases plasma insulin and decreases plasma glucose and adrenaline in non-insulin dependent (Type II) diabetic subjects. The hypoglycaemic effect was also evident in the presence of a high plasma glucose level produced by Biostator changing glucose infusion from 20.2 +/- 2.8 to 26.4 +/- 4.2 mg.kg-1.min-1 (p less than 0.01), and it was potentiated by simultaneous infusion of arginine. No additional effect of sparteine on the peripheral sensitivity to insulin were detected by the euglycaemic, hyperinsulinaemic glucose clamp technique, as the glucose infusion rate (3.1 +/- 0.8 vs 2.6 +/- 1.2 mg.kg-1.min-1) was not statistically significant different in the last 60 min of the experiment. It is concluded that sparteine sulphate enhances beta-cell secretion, causing a fall in the plasma glucose concentration.

Adult↗
PubMed1985

Inter-ethnic difference in sparteine oxidation among Ghanaians and Germans.

Sparteine oxidation, which exhibits genetic polymorphism in various Caucasian populations, was studied in 154 unrelated Ghanaian subjects. Mean total urinary recovery of sparteine and 2- and 5-dehydrosparteines (56.6 +/- 16.6% of the dose) was not different from Caucasians. In contrast to Caucasians, amongst whom 6.3 to 9% of the population are poor metabolizers (PM), no PM subject was observed in the Ghanaian population sample. The data appear to indicate allelic differences between Caucasians and Ghanaians in the gene encoding the synthesis of the P-450 isozyme involved in polymorphic sparteine oxidation.

Black People↗
PubMed1996

Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects.

OBJECTIVE: Codeine O-demethylation to morphine is catalysed by the genetic polymorphic sparteine oxygenase (CYP2D6). The objective of the present study was to assess the analgesic effect of codeine on different types of experimental pain in relation to sparteine phenotype. METHODS: Fourteen extensive (EMs) and 14 poor metabolizers (PMs) of sparteine completed a randomized, double-blind, three-way, cross-over study with a single oral dose of codeine (75 or 100 mg) against morphine (20 or 30 mg) and placebo. Pain tests performed before and 1, 2, 3, and 4 h after medication included the cold pressor test and pain thresholds for heat and pressure stimulation. Adverse effects were rated by a structured interview. RESULTS: After morphine, morphine and morphine-6-glucuronide were present in equal amounts in plasma of PMs and EMs. After codeine, neither morphine nor morphine-6-glucuronide could be detected in 13 of the 14 PMs, whereas at least one of the compounds could be detected in all EMs. Peak pain and discomfort rated on a VAS scale during the cold pressor test were significantly reduced by morphine in both EMs and PMs, with a median peak change of 8.5 and 7.0 mm, respectively, for peak pain, and 11.5 and 15.5 mm, respectively, for discomfort. Codeine only reduced these pain measures significantly in EMs, with a median peak change of 5.5 mm for peak pain and 10.5 mm for discomfort. Pain detection and tolerance thresholds to heat and pressure were not consistently altered by either morphine or codeine. In PMs, adverse effects were significantly more pronounced on morphine than on codeine and only showed a slight difference between codeine and placebo. In EMs, there was no difference between codeine and morphine and more pronounced adverse effects on both drugs as compared to placebo. CONCLUSION: This study confirms that codeine O-demethylation depends on CYP2D6; it shows that the 6-glucuronidation of morphine is independent of CYP2D6; it supports the theory that the analgesic effect of codeine depends on its O-demethylation; and it indicates that this is probably also the case for the adverse effects. The results lend no support to the suggestion of a non-opioid analgesic effect of codeine.

Adult↗
PubMed1982

Interaction of alkaloids with plant transfer ribonucleic acids. Effect of sparteine on lupin arginyl-tRNA formation.

The effect of the alkaloid sparteine on arginyl-tRNA formation was studied. It was demonstrated that sparteine sulfate in the concentration range 10-60 mM inhibits the charging reaction when amino acid, ATP and tRNA are used as variable substrates. The mode of action is different for all pattern of inhibition for all varied substrates is generally uncompetitive. A pattern of inhibition for all varied substrates is generally uncompetitive. A non-competitive mechanism for amino acid and tRNA was observed at low sparteine concentration, but in the case of ATP it is also uncompetitive.

Alkaloids↗
PubMed1978

Effect of sparteine sulfate on uterine prostaglandin F in the rat.

Indomethacin, an inhibitor of prostaglandin synthetase, added to an in vitro bath in a concentration of 1, 5, and 10 X 10(-6) g/ml reduced sparteine-induced contractions of isolated uterine segments from pregnant rats. Contractions induced by prostaglandin F2alpha and acetylcholine were not reduced. Sparteine increased the prostaglandin F content of the blood and uterine tissue in the pregnant but not in the nonpregnant rat. This increase was significantly reduced by the administration of indomethacin (10 mg/kg). The present study suggests that the mechanism of sparteine action is mediated through a prostaglandin F system.

Acetylcholine↗
PubMed2001

Kinetics and mechanism of the (-)-sparteine-mediated deprotonation of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine.

The (-)-sparteine-mediated asymmetric lithiation-substitution of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine ((E)-5) to afford gamma-substituted enantiomerically enriched products 6 is reported. The solution structure for the lithiated intermediate 8.1 in these reactions was determined by heteronuclear NMR to be a configurationally stable, alpha-lithio, eta(1)-coordinated monomer. This intermediate is proposed to exist as two rotamers that are rapidly equilibrating on the NMR time scale; competitive electrophilic substitution of each conformation results in the formation of Z or E products. Kinetic measurements of the lithiation by in situ infrared spectroscopy provide pseudo-first-order rate constants for reactions with a variety of concentrations of amine, (-)-sparteine, and n-BuLi. The reaction is first order in amine and zero order in 1:1 base--ligand complex. When the concentration of n-BuLi is varied independently of (-)-sparteine concentration, the reaction rate exhibits an inverse dependence on n-BuLi concentration. The deuterium isotope effect for the reaction was determined to be 86 at -75 degrees C, a result consistent with C--H bond breaking in the rate-determining step and indicative of tunneling. A reaction pathway involving a prelithiation complex is supported by kinetic simulations.

Allylamine↗
PubMed2004

An experimental and computational study of the enantioselective lithiation of N-Boc-pyrrolidine using sparteine-like chiral diamines.

The enantioselective lithiation of N-Boc-pyrrolidine using sec-butyllithium and isopropyllithium in the presence of sparteine-like diamines has been studied experimentally and computationally at various theoretical levels through to B3P86/6-31G*. Of the (-)-cytisine-derived diamines (N-Me, N-Et, N-(n)Bu, N-CH(2)(t)Bu, N-(i)Pr) studied experimentally, the highest enantioselectivity (er 95:5) was observed with the least sterically hindered N-Me-substituted diamine, leading to preferential removal of the pro-R proton i.e., opposite enantioselectivity to (-)-sparteine. The experimental result with the N-Me-substituted diamine correlated well with the computational results: at the B3P86/6-31G* level, the sense of induction was correctly predicted; the lowest energy complex of isopropyllithium/diamine/N-Boc-pyrrolidine also had the lowest activation energy (DeltaH++ = 11.1 kcal/mol, DeltaG++= 11.5 kcal/mol) for proton transfer. The computational results with the N-(i)Pr-substituted diamine identified a transition state for proton transfer with activation energies of DeltaH++= 11.7 kcal/mol and DeltaG++= 11.8 kcal/mol (at the B3P86/6-31G* level). Although comparable to (-)-sparteine and the N-Me-substituted diamine, these DeltaH++ and DeltaG++ values are at odds with the experimental observation that use of the N-(i)Pr-substituted diamine gave no product. It is suggested that steric crowding inhibits formation of the prelithiation complex rather than increasing the activation enthalpy for proton transfer in the transition state. Three other ligands (N-H and O-substituted as well as a five-membered ring analogue) were studied solely using computational methods, and the results predict that the observed enantioselectivity would be modest at best.

Computer Simulation↗
PubMed2005

Enantioselective lithiation of O-alkyl and O-alk-2-enyl Carbamates in the presence of (-)-sparteine and (-)-alpha-isosparteine. A theoretical study.

Quantum chemical DFT calculations at the B3LYP/6-31G(d) level have been used to study the enantioselective lithiation/deprotonation of O-alkyl and O-alk-2-enyl carbamates in the presence of (-)-sparteine and (-)-alpha-isosparteine. Complete geometry optimization of the precomplexes consisting of the carbamate, the chiral ligand, and the base (iPrLi), for the transition states of the proton-transfer reaction, and for the resulting lithio carbamates have been performed in order to quantify activation barriers and reaction energies. For the lithiodeprotonation of ethyl carbamate 12 in the presence of (-)-sparteine (5) the preferred abstraction of the pro-S proton (by 2.75 kcal/mol) gives the (S)-lithio derivate (S)-14, which is in good agreement with experimental observations. (-)-alpha-Isosparteine (6) is predicted to be significantly less selective favoring the abstraction of the pro-R proton by 1.2 kcal/mol. The O-alkenyl carbamate 17 as an example of an allylic carbamate is more easily lithiated than 12. As for 12 (-)-sparteine (5) favors the abstraction of the pro-S proton, although with smaller preference (0.7 kcal/mol). Structural parameters are discussed to rationalize the theoretical results.

Carbamates↗
PubMed1984

Sparteine oxidation by the human liver: absence of inhibition by mephenytoin.

Recent population data suggest independence of the genetic polymorphisms in mephenytoin and sparteine/debrisoquine oxidation. We used human liver preparations to test whether mephenytoin competes with sparteine for binding to the genetically variable cytochrome P-450, which mediates metabolism of both sparteine and debrisoquine. Mephenytoin failed to inhibit in vitro sparteine oxidation. This provides biochemical evidence that the polymorphism of sparteine/debrisoquine metabolism is not related to that of mephenytoin.

Binding, Competitive↗
PubMed1991

Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans.

The effects of quinidine on oxidative routes of drug metabolism mediated by different forms of cytochrome P450 were investigated in 10 healthy subjects. Each subject was studied on three different occasions and separately received oral administration of (1) a "cocktail" of nifedipine (5 mg), sparteine sulfate (90 mg), and mephenytoin (100 mg), (2) quinidine sulfate (200 mg), and (3) quinidine sulfate followed by the "cocktail" 1 hour later. Quinidine pretreatment significantly inhibited the aromatization of nifedipine to its major first-pass pyridine metabolite (M-0) and prolonged the elimination half-life of the calcium channel antagonist, both by about 40%. More marked inhibition of metabolism was observed with sparteine, and the formation of dehydrosparteine was abolished. A significant correlation was found between the 0-8-hour urinary ratio and the plasma concentration ratio of sparteine to dehydrosparteine obtained 4 hours after drug administration. No quinidine-induced changes were observed in the 4-hydroxylation of mephenytoin. The interaction between quinidine and nifedipine supports the involvement of a common P450 (P450IIIA4) in the metabolism of the two drugs.

Administration, Oral↗
PubMed2005

A synthesis of (+/-)-sparteine.

In a synthesis of racemic sparteine, Diels-Alder reaction between dimethyl bromomesaconate 14 and dicyclopentenyl 4, followed by cyclopropane formation, set up the stereochemistry at C-1 and C-5 as S and R, respectively, in a meso intermediate 8. The stereochemistry at C-2 and C-4 was then secured by a moderately diastereoselective protonation of the bis-enolate 17 derived from the diester 8 by reductive cleavage with lithium in liquid ammonia. The C=C in the racemic diester 19 was ozonolysed and the diketone converted by Beckmann rearrangement into the bis-lactam . Reduction of the bis-lactam with lithium aluminium hydride and intramolecular nucleophilic displacement gave racemic sparteine 1. Some ideas for making this synthesis amenable to a synthesis of enantiomerically enriched sparteine are presented.

Molecular Structure↗
PubMed1992

Evidence for a dissociation in the control of sparteine, debrisoquine and metoprolol metabolism in Nigerians.

The 0-8 hour urinary distributions of the metabolic ratios of sparteine (100 mg), debrisoquine (10 mg) and metoprolol (100 mg) were measured in 165 healthy, unrelated, black Nigerian medical students. There was a weak correlation (rs = 0.51, p < 0.001; n = 82) between the metoprolol/alpha-hydroxymetoprolol (M/HM) and the sparteine/total (2- + 5-) dehydrosparteine (S/DHS) ratios. No significant correlations were found between the debrisoquine/4-hydroxydebrisoquine (D/HD) and M/HM ratios (rs = 0.16, n = 33) and between the D/HD and S/DHS ratios (rs = 0.31, n = 38). Both visual inspection and kernel density analysis of the data suggested the presence of two phenotypic groups for sparteine oxidation, with 4% of the population studied being putative poor metabolizers. In contrast biomodality was not apparent in the distribution of the log10M/HM and log10D/HD ratios. These findings provide evidence for a dissociation in the control of metoprolol, sparteine and debrisoquine oxidation in Nigerians and highlight the difficulties in the interpretation of data from pharmacogenetic studies in different ethnic groups.

Adult↗
PubMed1994

The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes.

The impact of gender, use of oral contraceptive steroids (OCS), coffee consumption and of smoking on the metabolism of sparteine, caffeine, and paracetamol was studied in 194 randomly selected subjects (98 male and 95 female). Thirty-eight of the male volunteers were cigarette smokers, 40 of the female subjects were smokers and/or users of OCS. The metabolic ratio of sparteine oxidation (MRs) showed a trimodal distribution. 7.7% of the subjects had a MRs > 20 and thus were poor metabolizers (PMs). Within the extensive metabolizer (EM) subjects, a distinct subgroup accounting for 11% was observed with 20 > MRs > 1.2. Six of the 15 phenotypical PMs were heterozygous EMs by genotyping. This indicates the existence of one or several CYP2D6 mutations which cannot be identified by the currently employed genotyping methods. In each subgroup, i.e. smokers/OCS and non-smokers/non-OCS, the cumulative frequency distribution of the heterozygous (wt/B) phenotype caused a shift to higher MRs compared with the wild-type homozygotes (wt/wt). Thus, for the in vivo activity of CYP2D6, genetic determinants prevail over environmental factors. Smoking, use of oral contraceptive steroids, caffeine consumption, or gender had no influence on sparteine metabolism. The distribution of the paracetamol glucuronide/paracetamol metabolic ratio appeared to be unimodal although skewed. Glucuronidation capacity was clearly affected by gender, OCS use and smoking. It was higher in male than in female subjects. Male smokers had the highest, and female non-smokers/non-OCS users the lowest metabolic ratio. CYP1A2 activity, as determined by a caffeine metabolic ratio ((AFMU + 1X + 1U)/1, 7U), was multimodally distributed and was clearly increased in smokers. It was significantly correlated to paracetamol glucoronidation in male heavy smokers (r=0.85), suggesting an element of co-regulation of CYP1A2 and of paracetamol conjugating UDP-glucuronosyltransferase isozymes, including UGTI.6.

Acetaminophen↗
PubMed1996

Imipramine metabolism in relation to the sparteine oxidation polymorphism--a family study.

The relationship between genetic polymorphism and imipramine metabolism has never been studied in a family study. A sparteine/mephenytoin test was carried out in 31 parents and 20 siblings of 18 Danish poor metabolizers of sparteine (PMs). One week later, each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by HPLC. There were 10 PMs (20%; 9.8-33%, 95% confidence interval) and 41 extensive metabolizers of sparteine (EMs) among parents and siblings. In 26 of the 28 PMs among probands and relatives, there were concordance between phenotype and genotype: D6-A/D6-D (n = 2), D6-A/D6-B (n = 5), D6-B/(n = 15) or D6-B/D6-D (n = 4). Two PMs were apparently heterozygous (EMs), D6-wt/D6-B. Accordingly, based on the present sample of 28 PMs the specificity of the genotype test was 100% and the sensitivity was 92.9%. Two EMs were homozygous dominant D6-wt/and 39 were heterozygous EMs; D6-wt/D6-D (n = 5), D6-wt/D6-B (n = 27), D6-wt/D6-A (n = 6), D6-wt/D6-wt* (unknown mutation) (n = 1). As previously reported in a population study the hydroxylation ratios (i.e. 2-hydroxymetabolite over parent compound) of imipramine were much lower in PMs than in EMs. This and the pedigrees confirmed the co-segregation of sparteine oxidation, imipramine 2-hydroxylation and the CYP2D6 genotype. None of the hydroxylation ratios could separate EMs and PMs completely, mainly because the 2-hydroxylation of imipramine also depends on P450s other than CYP2D6.

Adolescent↗
PubMed1990

Correlations among the metabolic ratios of three test probes (metoprolol, debrisoquine and sparteine) for genetically determined oxidation polymorphism in a Japanese population.

The study was aimed at defining the relationships among the oxidative capacities for three prototype drugs, metoprolol, debrisoquine and sparteine, used for assessing genetically determined polymorphism of drug oxidation in a Japanese population. Among 292 unrelated healthy Japanese subjects who had been defined as extensive (EMs, n = 291) or poor (PM, n = 1) metabolisers of metoprolol oxidation, 55 subjects (EMs = 54 and PM = 1) were selected. One PM of metoprolol oxidation was also identified as a PM not only of debrisoquine but also of sparteine, and no misclassification by the three phenotypic methods was observed. All three correlations among the metabolic ratios of the three test probes assessed by Spearman's rank test were highly significant (P less than 0.001). These findings indicate that in Japanese subjects the oxidation capacities of metoprolol, debrisoquine, and sparteine are closely related. It appears that in Japanese the polymorphic oxidation of the three drugs is co-regulated, either by the same enzyme or gene-controlling system.

Adolescent↗