Vincamine

354.44

354.44

216-576-3

996XVD0JHT

DTXSID9040134

Yellow crystals from acetone or methanol

C - Cardiovascular system

29399990

54.7

2.9

white to almost white fine crystalline powder

1.1640 (rough estimate)

232-233 °C

487.66°C (rough estimate)

261.6±30.1 °C

1.6500 (estimate)

In water, 62 mg/L @ 25 deg C /Estimated/

2-8°C

1.1X10-12 mm Hg @ 25 deg C /Estimated/

LD50 in mice (mg/kg): 75 i.v.; >1000 s.c. (Szporny, Szász); 1000 orally (Szabo, Nagy)

42.8 º (c=1 in pyridine)

Henry's Law constant = 2X10-12 atm-cu m/mol @ 25 °C /Estimated/

180.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 2.6X10-10 cu cm/molec-sec @ 25 °C /Estimated/

NONH for all modes of transport

3

22

36-26

YY8575000

Xn

Stable under normal temperatures and pressures.

P301 + P312 + P330

H302

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 45 companies from 2 notifications to the ECHA C&L Inventory.

Vincamine in low concentrations induced a sustained contraction of the isolated guinea pig trachealis with long latency and slow onset and, in high concentrations, it induced relaxation which was potentiated in the precontracted trachealis. ...The vincamine-induced trachealis contraction was not changed by substance P desensitization, was reduced by tetrodotoxin, nifedipine and low Ca2+ high Mg2+ solution and increased in nominally Ca2+-free solution. The vincamine-induced relaxation of precontracted trachealis was increased by guanethidine and was not affected by propranolol, high Mg2+-low Ca2+ solution and tetrodotoxin. Vincamine- and vinpocetine-induced trachealis contraction as well as vinpocetine-induced relaxation at basal tension were abolished by indomethacin.

LD50 Mouse iv 75 mg/kg|LD50 Mouse sc >1,000 mg/kg|LD50 Mouse oral 1,000 mg/kg|LD50 Rat ip 253 mg/kg|For more Non-Human Toxicity Values (Complete) data for VINCAMINE (6 total), please visit the HSDB record page.

Periwinkle is used for circulatory disorders, cerebral circulatory impairment, support for the metabolism of the brain and its improved oxygen supply, prophylaxis of memory and concentration impairment, improvement of memory and thinking capacity, mental productivity, prevention of premature aging of brain cells, for geriatric support, as a sedative and as a blood pressure-lowering remedy, for catarrhs, feebleness, and for improvement of the immune function, for diarrhea, vaginal flux, throat aliments, tonsillitis and angina, sore throat, intestinal inflammation, toothache, dropsy, as a diuretic and blood-purifying remedy, for promotion of wound healing, as a hemostatic remedy, and a bitter principle.|Its use is recommended as a cerebral vasodilator in neonatal calves for cerebral anoxia.|/VET:/ Vincamine is widely used in human medicine to increase global and regional blood flow in patients suffering from acute or subchronic cerebral ischemia.|/VET:/ It is mostly used in combination with heptaminol (a central nervous system stimulant) and papaverine (a vasodilator).

...Vincamine and vincamine derivatives, ...are able to prevent the occurrence of an edematous reaction.|In animal experiments, administration of periwinkle caused destruction of blood components, manifested as leukocytopenia, lymphocytopenia, and lowering of the a a2-, and g-globulin level.|Arrhythmia was observed in rabbits and dogs after intravenous administration of doses of 0.5 to 2.5 mg/kg bw. However, this effect was not only a function of the dose but also of the speed of the infusion. When the speed of the infusion was higher than the rate of metabolic transformation, the effect on the heart increased even up to the death of the animal. The effect was linear with the dose and was present at all speeds of infusion used.|Sedative effects were established in mice after subcutaneous administration of doses of 2.5 to 10 mg/kg bw.|Other observed effects of vincamine include cardiovascular effects (e.g. hypotension, proarrhythmogenic effect) and effects on central nervous system (sedation).

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)|Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)

In a crossover study of six healthy volunteers the pharmacokinetics and the bioavailability of vincamine were studied after administration of two oral forms. All subjects received an oral dose of 60 mg vincamine. ...The drug generally follows a one-compartment kinetic model. The average value of Tmax is 1.4 +/- 0.5/hr with the tablets and 1 +/- 0.6/hr with the solution; the Cmax are, respectively, 155 +/- 82 micrograms . 1(-1) and 133 +/- 104 micrograms . 1(-1). The AUC are 443 +/- 156 micrograms . 1(-1) hr with the tablets and 315 +/- 178 micrograms . 1(-1) hr with the solution.|Vincamine HCl was biopharmaceutically and pharmacokinetically evaluated. For biopharmaceutical characterization of the drug the apparent lipoid/water partition coefficient (APC), pKa, extent of protein (bovine) binding and the erythrocyte (human) uptake were determined. Vincamine has an APC of 2.05, a pKa of 6.17, is 64% bound to plasma proteins, and is about 6% bound to erythrocytes. Because the gerbil was used as model in pharmacodynamic studies, the pharmacokinetic drug disposition was determined in this species and compared to parameters reported in the literature for other species. The terminal half-life is about 1 hour, the apparent volume of distribution 2.9 L/kg, and the total clearance is about 33.3 mL/min/kg. The parameters are comparable to other species including man. The brain concentration is about 5-fold that in plasma. A therapeutic steady state concentration for effectiveness in gerbils has been estimated to be 0.02 ug/mL.|Pharmacokinetic parameters of vincamine in rats were measured after oral administration of 20 mg base/kg bw and intravenous injection of 10 mg vincamine hydrochloride/kg bw. After oral administration, a bioavailability of 58% was found and the concentration/time curve showed a two-compartment open model. The following parameters were observed: an elimination half-life of 1.71 hours, a t-max of 1.27 hours, a C-max of 0.87 ug/ml, a total clearance of 0.818 1/h (higher than the plasma perfusion volume, which indicates a very quick metabolism in other organs in addition to the liver), and a volume of distribution of 2.018 liters. The amount of unchanged vincamine excreted was very low with 3 to 11% in urine and 2 to 5% in bile. Vincamine is taken up in high concentrations into the different organs resulting in the following ratios: lung/plasma 21, brain/plasma 14.6, kidneys/plasma 14.3, liver/plasma 8.9, heart/plasma 7.6. However, elimination from these organs was significantly more rapid than from plasma. After intravenous injection the pharmacokinetic parameters observed were an elimination half-life of 1.68 hours, a C-max of 5.46 ug/ml, a total clearance of 0.866 1/hour, and a volume of distribution of 2.104 liters. The values for elimination half-life, volume of distribution and total clearance did not differ significantly between oral and intravenous administration.|Pharmacokinetics of vincamine in dogs also followed a two-compartment open model. Doses of 10, 20 and 40 mg intravenously showed dose-dependent half-life and clearance rate. After oral administration of 20 mg vincamine hydrochloride, bioavailability ranged between 23 and 58%. Vincamine could be detected in the urine at up to 9.5% depending on urinary pH.|For more Absorption, Distribution and Excretion (Complete) data for VINCAMINE (6 total), please visit the HSDB record page.

The metabolism of vincamine hydrochloride was studied in the rat after oral administration of the drug. Vincamine is almost completely metabolized, only a small fraction of the original compound being excreted in the urine. The metabolites detected in blood, urine and tissues were purified by preparative thin layer and column chromatography in several solvent systems, and analyzed by mass spectrometry. It was found that the main urinary metabolites were vincamine conjugates (sulphates and glucuronides). Two new metabolites were detected in all the biological fluids and specimens analyzed: these compounds are more polar than vincamine and their structure was characterized by mass spectrometry, I.R. and U.V. spectroscopy and confirmed by synthesis in our laboratory.[Vigano V et al; Farmaco|Vincamine is very extensively metabolised with only a small percentage of unchanged compound detectable in the urine. Radiolabel studies in rats after an oral dose of 10 mg/kg bw demonstrate the metabolic pathway of vincamine. On the one hand it is hydrolysed by the plasma esterases to the unstable vincaminic acid. The latter is quickly decarboxylised and oxidised to eburnamenine. On the other hand vincamine is hydroxylated to the major metabolite 6-beta-hydroxy-vincamine, which accounts for 40% of total urinary and biliary radioactivity, followed by 6-alpha-hydroxy-vtncamine (8%) and 6-keto-vincamine, the oxidized metabolite of both previous metabolites (about 10% of the administered dose). 6-Keto-vincamine is eliminated by conjugation. The same metabolites (hydroxy.-keto) could also be detected in the urine of rabbits, dogs and man. Within 72 hours 40% of the total radioactivity are excreted in twine and 23% in the feces.

After intravenous injection /of vincamine hydrochloride to rats/ the pharmacokinetic parameters observed were an elimination half-life of 1.68 hours /Vincamine hydrochloride/.|The following parameters were observed /after oral administration of 20 mg/kg vincamine (base) to rats/: an elimination half-life of 1.71 hours...|After oral administration of 4 mg vincamine hydrochloride/kg bw /in dogs/ an elimination half-life of 4.5 hours (longer than for rats) and a total clearance of 0.52 1/hour were observed. /vincamine hydrochloride/|Half-life of elimination for the solution was 0.57 to 1.07 hours/for 169 mg vincamine hydrochloride and 33.81 mg vincamine hydrochloride control-released tablets respectively/.|Vincamine HCl was biopharmaceutically and pharmacokinetically evaluated. ...The terminal half-life is about 1 hour... .

... At concentrations of 1, 10 and 100 microM, a five-minute perfusion with vincamine did not affect the synaptically-mediated activation of pyramidal neurons evoked by stimulation of the Schaffer-commissural fiber system. The effect of vincamine on the excitability of the pyramidal neurons was investigated by studying its effect on the antidromically-elicited field potential and the input-output relation of Schaffer-commissural fiber input. No effect on either of the two parameters was seen at a concentration of 100 microM of vincamine. Vincamine ... attenuate both the post-tetanic (PTP) and long-term potentiation (LTP) evoked by repetitive stimulation of the Schaffer-commissural fiber system. At a concentration of 100 microM of vincamine, PTP was significantly reduced and LTP was almost completely suppressed.|Vincamine's function and therapeutic use as a vasodilating agent, especially at the level of the central nervous system, has been proven after an intravenous administration of 30 mg over a period of 20 minutes in Mongolian gerbils by an increase of cerebral blood flow of approximately 10% and of regional cerebral blood flow in areas with insufficient blood supply by approximately 15%. The mechanism of this vascular action, while not fully clear, seems to be partly due to a reserpine-like noradrenaline depleting effect. Hence, its sedative effects are similar to reserpine

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Presentation depends on the active toxic agent. In most cases, vomiting, abdominal pain, and diarrhea occur within 60 to 90 minutes of significant ingestion. With some toxins, severe gastroenteritis may result in massive fluid and electrolyte loss. ... Maintain open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, arrhythmias, and hypotension if they occur. Replace fluid loss caused by gastroenteritis with intravenous crystalloid solutions. ... Administer activated charcoal if available ... Gastric emptying is not necessary if activated charcoal is given promptly. /Plants and Herbal Medicines: Group 1/

/SIGNS AND SYMPTOMS/ Other observed effects of vincamine include cardiovascular effects (e.g. hypotension, proarrhythmogenic effect) and effects on central nervous system (sedation).|/CASE REPORTS/ Six patients developed ventricular arrhythmias with parenteral administration of vincamine. Direct intravenous injection was the mode of administration in 2 cases, intravenous infusion in 3 cases (one at very high dosage) and intramuscular injection in 1 case. The same signs of toxicity were observed in all patients:--5 patients had recorded attacks of "torsades de pointe", which recurred in 1 of them when the drug was restarted.--1 patient had syncope and, although an ECG was not recorded at the time, an ECG shortly afterwards showed a long QT interval and R/T ventricular extrasystoles. Symptoms were generally neurological in nature with syncope, cyanosis, and convulsions. Spontaneous regression was observed in 3 cases but in the others the drug had to be stopped and cardiopulmonary resuscitation instituted. None of our patients died of their arrhythmia.|/EPIDEMIOLOGY STUDIES/ This trial was performed to investigate the therapeutic efficacy of vincamine in the treatment of primary degenerative and vascular dementia. 152 male and female patients aged between 50 and 85 years from two psychogeriatric centers and two nursing homes were initially included in the trial and screened for eligibility. 142 patients completed the trial. ...In a 12-wk double-blind treatment either 30 mg vincamine or placebo was given twice daily. ...The therapeutic efficacy of vincamine was clearly demonstrated by confirmatory analysis as the drug was statistically significantly superior to placebo in all four target variables. The clinical relevance of the outcome was further underlined by the results of the responder analysis of the variables /Sandoz Clinical Assessment Geriatric scale/ (SCAG), /the subscale 'need for help' of the nurse's rating of geriatric patients (Beurteilungsskala fur geriatrische Patienten (Evaluation scale for geriatric patients);/ BGP) and /Short Cognitive Performance Test (Syndrom-Kurztest;/ SKT). Based on the results of this trial, it can be accepted that the therapeutic effect of vincamine is superior to placebo in patients with mild to moderate dementia of degenerative and vascular etiologies.

Cerebroxine

Pyrrolizidine alkaloids may be estimated in animal tissues and fluids by removing protein, chromatographing on Florisil and estimating colorimetrically with methyl orange. /Pyrrolizidine Alkaloids/