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Pharmacology: Pharmacodynamics: Nicergoline is an ergoline derivative with alpha-1 adrenergic blocking activity, when administered parenterally. After oral administration, the product undergoes a rapid and extensive metabolism, from which a series of metabolites originates, also responsible for the activities observed at several CNS levels.
Orally administered, nicergoline exerts multiple neuropharmacological actions: Not only it enhances the cerebral glucose uptake and consumption, the protein and nucleic acid biosynthesis, but it seems to act on various neurotransmitter systems.
Nicergoline improves the cerebral cholinergic functions in aged animals. Chronic nicergoline treatment in aged rats prevented the age-related reduction of Ach levels (in the cortex and in the striatum) and of release (in the hippocampus) in vivo. Increased CAT (choline-acetyltransferase) activity and muscarinic receptor density were also observed after chronic oral treatment with nicergoline. Furthermore, in both in vitro and in vivo experiments nicergoline significantly decreases AchE (acetylcholine esterase) activity. In these experiments the neurochemical effects were parallel with consistent behavioral improvements, for example in the maze test, where chronic nicergoline treatment in aged animals induced a response similar to that of younger animals.
Nicergoline was also able to improve the cognitive deficit induced by several agents (hypoxia, ECT, scopolamine) in animals. Low doses of nicergoline administered orally increase dopamine turnover in aged animals, particularly in the mesolimbic area, probably by modulating dopaminergic receptors. Nicergoline improves the cellular signal transduction mechanisms in aged animals. Both single and chronic oral treatment increased the basal and agonist-sensitive phosphoinositide turnover. Nicergoline also increases the activity and the translocation to the membrane compartment of the Ca-dependent PKC isoforms. These enzymes participate in the secretion mechanism of soluble amyloid precursor protein (APP) which leads to the increase of its release and the reduction of abnormal beta-amyloid production, as it was demonstrated in human neuroblastoma cultures.
Its antioxidant effect and by activating the detoxication enzymes, nicergoline prevents nerve cells from oxidative stress-caused death and from apoptosis in both in vivo and in vitro experimental models. Nicergoline reduces the age-related decrease of neuronal Nitric Oxide Synthase (nNOS) mRNA expression, which may contribute to the improvement of the cognitive function.
Human experiments: Human pharmacodynamic studies using computerized EEG techniques have been performed in young and aged volunteers as well as in elderly patients with cognitive disorders. Nicergoline had a normalizing effect on the EEG of elderly patients and younger adults under hypoxia, increasing α and β activity and decreasing δ and θ activity. Positive changes in event contingent potential and evoked reaction have been recorded in patients affected by mild to moderate dementia of various origin (SDAT and MID), following nicergoline chronic treatment (2-6 months), these changes are correlated with the improvement of clinical symptoms.
Based on the previously mentioned, it is obvious that nicergoline acts by the broad-spectrum modulation of cellular and molecular mechanisms involved in the pathophysiology of dementia.
In double-blind, placebo-controlled clinical studies more than 1500 patients were involved with dementia (Alzheimer's type, vascular and mixed type dementia) receiving 60 mg nicergoline per day or placebo. Following long-term nicergoline treatment, a continuous improvement in cognitive and behavioral disturbances associated with dementia were observed. The change could be observed after 2 months of treatment and were permanent during one year treatment.
Pharmacokinetics: Absorption: Nicergoline is rapidly and almost completely absorbed following oral administration. The peak serum radioactivity after administration of low doses (4-5 mg) of radioactive H3 labelled nicergoline to healthy volunteers occurred in 1.5 hours post-dose. However therapeutic oral doses (30 mg) of C14 labelled nicergoline in healthy volunteers showed peak serum radioactivity in 3 hours post-dose.
After oral administration of nicergoline (15 mg) in healthy volunteers, the area under the curve of plasma radioactivity (AUC) for main active metabolite MDL and the second active metabolite MMDL were 81% and 6% of AUC of total radioactivity, respectively. Peak plasma levels of MDL following administration of 30 mg tablet as single dose or multiple doses were achieved approximately 3-5 hours post-dose. Peak plasma levels of MMDL following administration of a single dose of 30 mg tablet were generally achieved approximately 0.5 to 1 hour post-dose.
The absolute bioavailability of nicergoline following oral administration is approximately 5% of the administered dose, because of its first-pass metabolism.
The pharmacokinetics of nicergoline in healthy volunteers following oral doses of 30-60 mg were found to be linear based on measurement of its principal metabolite MDL.
There was no relevant food effect on the pharmacokinetics of MDL and MMDL when nicergoline was given as a single oral dose of 30 mg tablet.
Distribution: Nicergoline distribution to tissues is rapid and extensive, as reflected by the short distribution phase of plasma radioactivity. The nicergoline volume of distribution in central compartment (roughly estimated by dividing the dose by nicergoline plasma concentration at the first PK sampling time after IV administration of nominal 2 mg dose) is fairly high (224 L), which possibly reflects nicergoline distribution into blood cells and/or tissues.
Nicergoline is extensively bound to human plasma proteins, with 4-fold higher affinity for α-acid glycoprotein than for serum albumin. The percentage binding is relative constant when nicergoline concentration is increased from 1 μg/mL to 500 μg/mL. Both nicergoline metabolites, MDL and MMDL, have low protein binding values of approximately 14.7% and 34.7% in a concentration range of 50-200 ng/mL, respectively.
Metabolism and Elimination: Urinary excretion is the main elimination route. Within 120 hours post-dose, average of 82% of the total radiolabelled nicergoline dose is excreted via the kidney and 10% via feces. Nicergoline is extensively metabolized. Its main metabolic route is via hydrolysis of the ester bond, producing MMDL, and then by the formation of MDL via demethylation. The demethylation process occurs through the catalytic action of the isoenzyme CYP2D6. Therefore, pharmacokinetics of nicergoline and its metabolites are affected in subjects with a genetic deficit of cytochrome CYP2D6. The resulting active metabolites (MMDL and MDL) are conjugated with glucoronic acid. The main metabolite MDL accounts for 51% of the total dose and 76% of radioactivity recovered from urine following an oral dose of 15 mg. The mean value of terminal half-life for MDL ranged approximately 11-20 hours.
Special Population: The effect of renal impairment on the pharmacokinetics of nicergoline was evaluated in patients with mild (Clcr 60-80 mL/min), moderate (Clcr 30-50 mL/min), and severe (Clcr 10-25 mL/min) renal impairment. In the patients with mild (n=5), moderate (n=5), and severe (n=4) renal impairment, significant differences were observed in the amount of MDL excreted in urine within 120 hours after a 30 mg oral dose of nicergoline (38.1%, 42.6%, and 25.7% of the dose, respectively); for MMDL, the corresponding values were 1.7, 0.6, and 0.2%, respectively. Patients with severe renal impairment exhibited a significant decrease in urinary MDL excretion compared to the other two groups. In addition, patients with mild, moderate, and severe renal impairment showed an average decrease in MDL urinary excretion (0-72 hours) of 32%, 32%, and 59% compared with the subjects with normal renal function in another study with 30 mg tablet.
The pharmacokinetics of nicergoline has not been studied in patients with hepatic impairment.
The pharmacokinetics of nicergoline has not been studied in children.
The influence of age (geriatric) on the pharmacokinetics of nicergoline has not been fully studied.
Toxicology: Preclinical safety data: Carcinogenicity studies have not been conducted. Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity, and embryo-fetal, and peri- and postnatal development. In a fertility study, nicergoline had no effect on male fertility at doses of up to 50 mg/kg/day (8 times the maximum recommended human dose of 60 mg/day on a mg/m2 basis). In female rats administered 50 mg/kg/day, there was a significantly reduced pregnancy rate and at the Gestation Day 13 cesarean section, there was a significantly lower number of corpora lutea and lower number of implants and embryos. However, there were no effects on litters of treated females that delivered in this study.
30 mg film-coated tablet: Acute, subacute and chronic toxicity studies in various animal species (rat, dog and rabbit) have shown that the drug is well tolerated. In addition, nicergoline has no teratogenic and embryotoxic effects and is not mutagenic. Numerous controlled clinical studies carried out with appropriate methodologies in patients affected by cerebral deterioration have shown that nicergoline is effective in ameliorating the cognitive, affective behavioral and somatic disturbances associated with this disease.
