Assessing the genotoxicities of sparteine and compounds isolated from Lupinus mexicanus and L. montanus seeds by using comet assay.

The genus Lupinus is widely distributed. Its seeds are used for animal and human food, and Lupinus possesses pharmacological potential because of its high content of quinolizidine alkaloids and flavonoids; however, there is little available information about its genotoxicity. We used the comet assay and staminal nuclei of Tradescantia (clone 4430) to evaluate the in vitro genotoxicity of 4 concentrations (0.01, 0.1, 0.5, and 1.0 mM) of alkaloid extracts of Lupinus mexicanus and Lupinus montanus, flavonoids of L. mexicanus, and commercial sparteine; nitrosodiethylamine was used as a positive control and untreated nuclei were used as a negative control. All concentrations of L. mexicanus and L. montanus showed significant genotoxic activity (P ≤ 0.05). A similar behavior was observed for flavonoid extracts of L. montanus except the 1.0 mM concentration. Sparteine showed genotoxic activity only at 0.5 mM. The order of genotoxicity of the compounds studied was as follows: L. mexicanus > L. montanus > flavonoids of L. montanus > sparteine. There is evident genotoxic activity in the compounds that were studied, particularly at lower concentrations (0.01 and 0.1 mM). Given the limited information about the genotoxicity of the compounds of L. mexicanus and L. montanus, further studies are necessary.

[Derivatives of lupinin and epilupinin as ligands of various cholinesterases].

Literature data have been summarized on interaction of cholinesterases of some mammals and arthropods with a group of isomer derivatives of alkaloid lupini and its epimer epilupinin. As substrates of cholinesterases of several mammals there are studied 8 acetates containing in their molecules the chinolysidin bicycle with different structure of N-alkyl radical, which showed certain elements of specificity of action. For 2 isomer esters that are derivatives of the protonated base of the lupinin and epilupinin structures, differences in their substrate characteristics were revealed. The polyenzyme analysis if anticholinesterase efficiency was performed for 30 organophosphorus inhibitors that are dialkoxyphosphorus derivatives of lupinin and epilupinin; as a result, quite a few peculiarities of their action depending on their structure were revealed. Several tested compounds turned out to act as specific inhibitors of cholinesterases of some mammals and arthropods.

Esparteína y lupanina: dos alcaloides quinolizidínicos de las especies lupinus eremonomos y L. meridanus M / Sparteine and lupanine two quinolizidine alkaloids from lupinos eremonomos S. and L.meridanus M

Los géneros de la familia leguminosae se caracterizan por contener alcaloides con esqueleto quinolizidínico. Entre ellos se encuentra el género Lupinos, el cual está representado en Venezuela por varias especies, poco estudiadas botánicamente. En este trabajo se presentan los resultados obtenidos del estudiante de los alcaloides de Lupinos eremonomos S. y L. meridanus Mortiz

Adverse drug reaction reporting and retrospective phenotyping for oxidation polymorphism.

A genetically determined impairment in the ability to oxidase sparteine and debrisoquine also affects the oxidation of several other drugs. This impairment in oxidation may result in accumulation of the associated drugs and in an increased susceptibility to adverse reactions from these drugs. Dunedin houses the New Zealand national centre for the collation and study of adverse drug reactions. Included among the reporting schemes is an intensified monitoring system for newly released drugs, in which physicians report all clinical events occurring during treatment with the drugs under surveillance. The centre thus has available extensive records of names and addresses of prescribers and patients who have been reported as experiencing an adverse event while receiving drug therapy. We investigated the association between genetically poor oxidation of sparteine and adverse reactions to drugs selected as possibly sharing the sparteine/debrisoquine oxidation pathway; these included perhexiline, metoprolol, debrisoquine, piroxicam, mianserin and nifedipine. A kit containing instructions, a sparteine capsule and a container for urine collection was sent to physicians who reported adverse reactions or events to one of the above drugs for forwarding to the patient. It appeared possible, after assays of returned urine for sparteine and its metabolites, that adverse reactions to nifedipine were associated with genetically poor oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Severe complications of antianginal drug therapy in a patient identified as a poor metabolizer of metoprolol, propafenone, diltiazem, and sparteine.

A 47-year-old patient suffering from coronary artery disease was admitted to the CCU in shock with III. AV block, severe hypotension, and impairment of ventricular function. One week prior to admission a therapy with standard doses of metoprolol (100 mg t.i.d. and then 100 mg b.i.d.) had been initiated. Two days before admission diltiazem (60 mg b.i.d.) was prescribed in addition. Analyses of a blood sample revealed unusually high plasma concentrations of metoprolol (greater than 3000 ng/ml) and diltiazem (526 ng/ml). The patient recovered within 1 week following discontinuation of antianginal therapy. Three months later the patient was exposed to a single dose of metoprolol, diltiazem, propafenone (since he had received this drug in the past), and sparteine (as a probe for the debrisoquine/sparteine type polymorphism of oxidative drug metabolism). It was found that he was a poor metabolizer of all four drugs, indicating that their metabolism is under the same genetic control. Therefore, patients belonging to the poor-metabolizer phenotype of sparteine/debrisoquine polymorphism in drug metabolism, which constitutes 6.4% of the German population, may experience adverse drug reactions when treated with standard doses of one of these drugs alone. Moreover, the coadministration of these frequently used drugs is expected to be especially harmful in this subgroup of patients.

La biotransformación de la esparteína en amerindios cunas de Panamá / Biotransformation of sparteine in Amerindians cunas of Panamá

Reportamos, por vez primera, un estudio de oxidación metabólica en un grupo amerindio: los cunas de Panamá. Estudios genéticos indican un escaso mestizaje de menos del 1% de mezcla racial y establecen la identidad genética del grupo cuna con respecto a otros grupos amerindios que se remonta, a lo menos, a 5,000 años. Ciento nueve voluntarios recibieron 50 mg de esparteína y recogieron sus orinas por 12 horas, para determinar la cantidad que contenían de esparteína y de sus dos productos de oxidación. El porcentaje del medicamento intacto recuperado de la orina, así como de sus metabolitos, fue menor que el encontrado en otros grupos étnicos y está normalmente distribuido. La razón metabólica, que es un índice de eficiencia de la actividad de la isozima involucrada en la biotransformación de la esparteína, indica que no existen metabolizadores deficientes en este grupo y que la frecuencia de los metabolizadores extensos muestra una distribución unimodal. Por esas razones concluimos diciendo que en el grupo cuna, a diferencia de los grupos caucasoides, no existe polimorfismo en la oxidación de la esparteína. Además la ausencia de metabolizadores deficientes entre los cunas indica que este grupo, en comparación con los caucasoides, se encuentra en menor riesgo de desarollar reacciones tóxicas al usar medicamentos que siguen la ruta de la esparteína

[Hypothalamic syndromes after the administration of toxic doses of drugs for terminating pregnancy]. / O gipotalamicheskikh sindromakh posle primeneniia toksicheskikh doz lekarstvennykh sredstv s tsel'iu prekrashcheniia beremennosti.

Twenty-five women presented with primary injuries of the hypothalamic area and the hypothalamic syndrome that resulted from the intake of toxic doses of drugs (TDD) for inducing an abortion. The situation was simulated in mature rats. Experiments evidenced a predominant involvement of the hypothalamic area, vs. other portions of the brain. All the patients developed the vegetovascular form of the hypothalamic syndrome, combined with neuroendocrine and thermoregulation disturbances. TDD-induced increase of the vulnerability of the hypothalamus during pregnancy may be explained by structural and functional peculiarities of the female hypothalamus, by suppression of the dominant gestational functional integrating system formed during pregnancy and simultaneous failure of the principal performance system, the hypothalamus.

PIP: An experiment on intake of toxic doses of drugs (TDD) was conducted in Russia on 27 mature white rats divided into 3 groups. The 1st group was given intramuscular injections of synestrol (10-15 mg/kg), pituitrin (5 mg/kg), pachycarpine (40-50 mg/kg) and quinine (200 mg/kg) outside the pregnancy phase. The 3rd group was in the pregnancy phase and given the same doses of these drugs. The 2nd group was in the pregnancy phase and not given these preparations. The control group consisted of 4 rats injected with a physiological solution in the amount of 2 mg/kg. The preparations were given over a 5-day period. After decapitation, the anterior and posterior sections of the hypothalamus and cerebral cortex were analyzed. It showed that structural and metabolic changes in the rats of the 1st group were represented equally both in the cerebral cortex and in the hypothalamic area. In the 3rd group, these changes were considerably greater in hypothalamic area than in the cerebral cortex. In the 2nd group, only minor metabolic changes were observed in the hypothalamic area, apparently caused by the pregnancy itself. All this proves that injection of TDD during pregnancy primarily affects the hypothalamic area. Twenty-five women with affection of the hypothalamic area, developing as a result of TDD intake (synestrol, pituitrin, pachycarpine and quinine) to terminate pregnancy. Duration of intake was 2-5 days. Clinical investigations, EEG's, cranial x-rays, and examination of the fundus of the eye and conditions of the autonomic nervous system were conducted on all the women. An autonomic-vascular form of hypothalamic syndrome was noted in all the patients, in all cases combined with minor neuroendocrine and thermoregulation disturbances. There also were observed innervation impairment of cranial nerves, changes in muscle tone, and asymmetry of deep reflexes. Hypertension syndrome was also determined in a number of cases. The emotional disorders which are typical of patients suffering from primary affection of the hypothalamic area should also be noted. Hypothalamic syndrome in the women did not develop immediately after taking TDD, but 2 weeks to 2 months later. There is reason to believe that during the pregnancy there is a heightened "vulnerability" of the hypothalamus as a result of changes in its functional state and activities. Intake of TDD to interrupt a pregnancy disturbs the activities of the hypothalamus and also the limbic system as a whole. The activities of the gestational integrative functional system are especially important during pregnancy. Intake of TDD results in structural and functional failure of the gestational functional system and its principal performance organ--the hypothalamus.

Termination of midtrimester pregnancies with extraovular 0.1% ethacridine lactate. Accurate method for estimation of blood loss. Role of spartein sulfate.

PIP: This study evaluated the effectiveness of extraovular .1% ethacridine lactate alone and edacridine lactate plus spartein sulfate in midtrimester pregnancy termination. In the 60 cases where ethacridine lactate alone was administered, 50 cases aborted within 48 hours of instillation (83.3% success rate). Of these 50, 25 aborted within 24 hours (41.7%). Abortion was complete in 45 cases. The time of onset of uterine contractions ranged from 1 hour to 16.5 hours, with a mean 21-1/4 hours. The mean time of membrane rupture in the series was 23 hours and the induction-abortion interval averaged 27-1/4 hours. Side effects included vomiting (18.3%), shivering (16.6%), fever (3.3%), cervical injuries (6.6%), and excessive blood loss (1.7%). Blood loss until expulsion of the fetus averaged 54.1 ml, and blood loss up to 4 hours after abortion averaged 115.1 ml in cases of complete abortion and 219 ml in cases of incomplete abortion. In the 90 cases where both ethacridine lactate and spartein sulfate were used, 76 aborted within 48 hours (success rate 84.6%) and 40 aborted within 24 hours (44.4%). Abortion was complete in 75% of cases. The abortion-induction interval ranged from 4 hours to 47-3/4 hours, with a mean of 28-1/2 hours. These results, which are comparable to those obtained in other studies, indicate that extraovular ethacridine lactate alone appears to be a safe, efficient, and relatively inexpensive method of midtrimester abortion. Although there were fewer reports of side effects in the group that received spartein sulfate, use of this compound does not reduce the induction-abortion interval. The relatively low incidence of side effects such as vomiting and diarrhea, the antiseptic properties of ethacridine lactate, and the absence of serious complications such as rupture of the uterus and cervicovaginal fistula are advantages of the ethacridine lactate method that nullify the disadvantage of its slightly prolonged induction-abortion interval.^ieng

[Effect of sparteine sulfate on the predamaged conduction system of the heart]. / Die Wirkung von Sparteinsulfat auf das vorgeschädigte Erregungsleitungssystem des Herzens

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.