Nicergoline

Pharmacological properties

nicergoline is a derivative of ergoline with α1-adrenergic blocking activity. after oral administration, nicergoline undergoes a rapid and significant metabolism with the formation of a number of metabolites, due to which activity at different levels of central nervous system is also observed.

With oral administration, Nicergoline exhibits numerous neuropharmacological effects: it not only increases the intake and consumption of glucose in the brain, enhances the biosynthesis of protein and nucleic acids, but also affects various neurotransmitter systems. Nicergoline improves cerebral cholinergic function in older animals. Long-term use of nicergoline in old rats prevented an age-related decrease in acetylcholine levels (in the cortex and striatum), and also reduced the release of acetylcholine (in the hippocampus) in vivo. After prolonged oral administration of nicergoline, an increase in the activity of cholinacetyltransferase and the density of muscarinic receptors was also noted. Moreover, in vitro and in vivo studies, nicergoline significantly increased acetylcholinesterase activity. In these experimental studies, neurochemical effects were observed simultaneously with a steady improvement in behavioral reactions, for example, in a labyrinth test in mature animals that had been using Nicergoline for a long time, the development of reactions similar to those in young animals was observed.

During the use of nicergoline in animals, it was also possible to reduce the severity of manifestations of cognitive deficiency, which was induced by several agents (hypoxia, electroconvulsive therapy, scopolamine). Low-dose oral administration of nicergoline increases dopamine metabolism in mature animals, in particular in the mesolimbic region, probably by modulating dopaminergic receptors. Nicergoline improves signal transduction mechanisms in cells in mature animals. Both after a single and long-term oral administration of the drug, an increase in the metabolism of basal and agonist-sensitive phosphoinositide was observed. Nicergoline also increases the activity and transfer to the membrane portion of calcium-dependent isoforms of protein kinase C. Due to its antioxidant effect and ability to activate detoxification enzymes, nicergoline prevents the death of nerve cells caused by oxidative stress and apoptosis. Nicergoline reduces the age-related decrease in the expression of mRNA of neuronal nitric oxide synthase, which can also affect the improvement of cognitive function.

Pharmacokinetics After oral administration, nicergoline is rapidly and almost completely absorbed. The maximum radioactivity after healthy volunteers took low doses (4–5 mg) of H-labeled nicergoline was determined after 1.5 hours. However, after oral administration of therapeutic doses (30 mg) of C-labeled nicergoline by healthy volunteers, the maximum serum radioactivity was observed after 3 hours after taking the dose. After oral administration of nicergoline (15 mg) by healthy volunteers, the area under the serum radioactivity curve was 81 and 6% of the value calculated for the two main metabolites of nicergoline, MDL and MMDL, respectively. Peak plasma concentrations of MDL were reached approximately 3-5 hours after a single or repeated use of a 30 mg tablet. Peak plasma MMDL concentrations were reached approximately 0.5–1 hours after a single 30 mg tablet.

The absolute bioavailability of nicergoline after oral administration is about 5% due to the effect of the first passage.Based on the results of determining the levels of the main metabolite of MDL, it was found that in healthy volunteers after oral administration of a dose of 30-60 mg, the pharmacokinetics of nicergoline is linear. After a single oral administration of nicergoline at a dose of 30 mg, a significant effect of food intake on the pharmacokinetics of MDL and MMDL was not detected.

The distribution of the drug in the tissues is fast and wide, which is reflected in the short phase of the distribution of radioactivity in blood plasma. The distribution volume of nicergoline in the central compartment (approximately calculated by dividing the dose by the concentration of nicergoline in blood plasma in the first period for sampling after iv administration of a nominal dose of 2 mg) is relatively high (224 L), which potentially reflects the distribution of nicergoline in blood cells and / or tissues. Nicergoline in significant quantities binds to human plasma proteins, while the affinity for α-acid glycoprotein is 4 times higher than for plasma albumin. The percentage of binding is relatively constant when the concentration of nicergoline rises from 1 to 500 μg / ml. Both nicergoline metabolites, MDL and MMDL, are characterized by low levels of binding, about 14.7 and 34.7%, respectively, in the concentration range of 50-200 ng / ml. Mostly the drug is excreted in the urine. Within 120 hours after application, about 82% of the total amount of radioisotope-labeled nicergoline is excreted by the kidneys, and 10% with feces. Nicergoline undergoes significant metabolism mainly by hydrolysis of ether bonds with the formation of MMDL, and then MDL by demethylation (using the catalytic action of the CYP 2D6 isoenzyme). Therefore, the pharmacokinetics of nicergoline and its metabolites is exposed in patients with a genetic deficiency of CYP 2D6. The active metabolites that form (MMDL and MDL) are conjugated to glucuronic acid. The main metabolite of MDL accounts for 51% of the total dose and 76% of the radioactivity determined in the urine after oral administration of a dose of 15 mg. The average value of the final T_½ MDL is in the range of 11–20 hours.

The effect of renal dysfunction on the pharmacokinetics of nicergoline was evaluated in patients with impaired renal function (creatinine clearance (Clcr) 60–80 ml / min), moderate (Clcr 30–50 ml / min) and severe (Clcr 10–25 ml / min) degrees. In patients with impaired renal function of mild (n = 5), moderate (n = 5) and severe (n = 4) degrees, significant differences were observed in the amount of MDL that was excreted in the urine within 120 hours after oral administration of nicergoline at a dose of 30 mg (38.1; 42.6 and 25.7% of the administered dose, respectively); for MMDL, the corresponding values ​​were 1.7; 0.6 and 0.2%. In patients with severe renal impairment, a significant decrease in urinary MDL excretion was noted compared with the other two groups. In addition, in patients with mild, moderate, or severe renal impairment, an average decrease in urinary MDL excretion (0–72 h) was observed by 32; 32 and 59%, respectively, compared with patients with normal renal function who participated in another study using 30 mg tablets.

The pharmacokinetics of nicergoline in patients with impaired liver function has not been studied.

The pharmacokinetics of nicergoline has not been studied in children.

The effect of age (in elderly patients) on the pharmacokinetics of nicergoline is not fully understood.

Indications

Acute and chronic cerebrovascular metabolic disorders due to atherosclerosis, thrombosis and embolism of cerebral vessels, transient disorders of cerebral circulation (transient ischemic attacks).

Headache.

As an additional therapy for hypertension.

Application

The recommended daily dose of the drug is 5-10 mg 3 times a day at regular intervals, preferably between meals, for continuous treatment.

Dosage regimens, duration of treatment and route of administration depend on the severity of individual clinical manifestations of the disease.

According to the results of studies of pharmacokinetics and tolerance in elderly patients, dose adjustment of the drug is not required.

Patients with impaired renal function. Since kidney excretion is the main route of excretion (80%) of nicergoline and its metabolites, it is recommended to reduce the dose for patients with impaired renal function (plasma creatinine level ≥2 mg / ml).

The effect of treatment is manifested gradually. Since the therapy is usually carried out for a long time, at least every 6 months the doctor should evaluate the appropriateness of continuing treatment.

Contraindications

Hypersensitivity to ergot alkaloids or any component of the drug. recent myocardial infarction, acute bleeding, orthostatic hypotension, severe bradycardia.

Side effects

Frequency categories are expressed as: very often (≥1 / 10); often (from ≥1 / 100 to 1/10); infrequently (from ≥1 / 1000 to 1/100); rarely (from ≥1 / 10,000 to 1/1000); very rarely (1/10 000); frequency is unknown (frequency cannot be determined based on available data).

In each group, the frequency of adverse reactions is presented in decreasing order of severity.

Mental disorders: infrequently - anxious agitation, confusion, insomnia.

Violations of the nervous system: infrequently - drowsiness, dizziness, headache; frequency unknown - sensation of heat.

Violations of the vessels: infrequently - arterial hypotension, hyperemia.

Disorders from the digestive tract: often - a feeling of discomfort in the abdomen; infrequently - diarrhea, nausea, constipation.

Violations of the skin and subcutaneous tissue: infrequently - itching; frequency unknown - rash.

General disorders and reactions at the injection site: frequency unknown - fibrosis.

Research results: infrequently - increased concentration of uric acid in the blood. There is evidence of an increase in the level of uric acid in the blood, which did not depend on the prescribed dose or on the duration of treatment.

special instructions

Studies with single or multiple use of nicergoline have shown that nicergoline can reduce systolic hell and, to a much lesser extent, diastolic hell in patients with normal and elevated hell. these effects may vary since other studies have not revealed changes in systolic or diastolic hell.

Patients taking nicergoline should be careful with sympathomimetics (α- and β-receptor agonists, see INTERACTIONS).

Caution should be used in patients with angina pectoris and severe atherosclerosis. At the beginning of treatment, orthostatic hypotension may develop.

The drug should be used with caution in patients with a history of hyperuricemia or gout and / or during concomitant treatment with drugs that can affect the metabolism and excretion of uric acid.

Since about 80% of the metabolites of nicergoline are excreted in the urine, it is advisable to reduce the dose in patients with impaired renal function (serum creatinine ≥2 mg / dl or 175 mmol / l).

The effect of the use of the drug increases gradually. Therefore, the drug must be taken for a long time. It is advisable that every 6 months the doctor assesses the effect and makes a decision regarding the advisability of further use of the drug.

At the time of use of the drug should refrain from drinking alcohol. The occurrence of fibrosis (e.g., fibrosis of the lungs, heart, heart valves, and retroperitoneal fibrosis) has been associated with the use of certain ergot alkaloids with 5-HT agonist activity_2β-receptors of serotonin.

Symptoms of ergotism (including nausea, vomiting, diarrhea, abdominal pain, and narrowing of peripheral vessels) have been reported with some ergot alkaloids and their derivatives.

Before prescribing this class of drugs, doctors need to familiarize themselves with the signs of an ergot overdose.

The drug should not be used in patients with hereditary galactose intolerance, lactase deficiency or glucose / galactose malabsorption syndrome.

Use during pregnancy and lactation. Available data do not confirm the teratogenic effect of nicergoline. Given the indications, the use of the drug in pregnant women and women who are breastfeeding is unlikely. During pregnancy, nicergoline should be used only in cases where the potential benefit to the patient exceeds the potential risks to the fetus.

It is not known whether nicergoline passes into breast milk, so it should not be used in breast-feeding women.

Nicergoline does not affect rat fertility.

Children. The drug is not used in children.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Although the clinical effects of nicergoline are used to improve attention and concentration, its effect on the ability to drive vehicles and other automated systems has not been studied. In any case, care must be taken, given the underlying disease of the patients. When driving or working with other automated systems, note that dizziness or drowsiness may occur from time to time (see ADVERSE EFFECTS).

Interactions

With caution, the drug is used simultaneously with:

• antihypertensive drugs: nicergoline may enhance their effect. Nicergoline may enhance the effect of β-adrenoreceptor blockers on the heart;
• sympathomimetics (α- and β-): nicergoline may have an antagonistic effect on the vasoconstrictor effect of sympathomimetics due to blocking of α-adrenergic receptors;
• drugs that are metabolized by the CYP 2D6 isoenzyme: since nicergoline is metabolized by the CYP 2D6 isoenzyme, interactions with other drugs that are metabolized in the same way cannot be ruled out;
• antiplatelet agents and anticoagulants (e.g. acetylsalicylic acid): enhances the effect on hemostasis, as a result of which bleeding time may increase;
• drugs that affect the metabolism of uric acid: nicergoline can lead to an asymptomatic increase in the concentration of uric acid in blood plasma.

Overdose

When using nicergoline in high doses, a temporary decrease in hell may be noted. special treatment is usually not required, it is enough to give the patient a lying position for several minutes. in exceptional cases of insufficient blood supply to the brain and heart, the use of sympathomimetics and constant monitoring of hell are recommended.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C.