Clinical efficacy and safety of nicergoline combined with oxiracetam in the treatment of vascular cognitive impairment.

As a α1-adrenergic receptor antagonist, nicergoline can induce vasodilation and increase arterial blood flow. Its clinical application can effectively prevent and treat cognitive impairment and reduce cognitive decline and comprehensively improve patients' daily living ability and social function. The clinical efficacy of nicergoline combined with oxiracetam in the treatment of vascular cognitive impairment after stroke was analyzed. 120 patients with cognitive impairment after stroke were randomly divided into nicergoline group and Experience group. They were treated with nicergoline and nicergoline combined with oxiracetam respectively. Both groups were treated for one month. Montreal Cognitive Assessment Scale (MoCA) was used to evaluate the cognitive function of the two groups before and after treatment, and the clinical efficacy was compared. The results showed that the average score of MoCA in the combined group was (5.97±2.06), higher than that in the nicergoline group (3.53±1.44). The change of MoCA score was the most significant. There was significant difference between the nicergoline group and the combined group (t=4.21, P<0.01). The combined group had the highest effective rate and the total effective rate was 93.3%. Conclusion: Nicergoline and oxiracetam are effective drugs in the treatment of vascular cognitive impairment (VCI). The combined use of nicergoline and oxiracetam is better than that of nicergoline alone. The combined use of nicergoline and oxiracetam can significantly improve the severity of symptoms and quality of life in patients with vascular cognitive impairment after stroke. The clinical effect is definite.

Therapeutic use of nicergoline.

The ergot alkaloid derivative nicergoline became clinically available about 35 years ago in the 1970s. Nicergoline has a broad spectrum of action: (i) as an alpha(1)-adrenoceptor antagonist, it induces vasodilation and increases arterial blood flow; (ii) it enhances cholinergic and catecholaminergic neurotransmitter function; (iii) it inhibits platelet aggregation; (iv) it promotes metabolic activity, resulting in increased utilization of oxygen and glucose; and (v) it has neurotrophic and antioxidant properties. Acting on several basic pathophysiological mechanisms, nicergoline has therapeutic potential in a number of disorders. This article provides an overview of the published clinical evidence relating to the efficacy and safety of nicergoline (30 mg twice daily) in the treatment of dementia (including Alzheimer's disease and vascular dementia) and vascular and balance disorders. For dementia of different aetiologies, the therapeutic benefit of nicergoline has been established, with up to 89% of patients showing improvements in cognition and behaviour. After as little as 2 months of treatment, symptom improvement is apparent compared with placebo, and most patients are still improved or stable after 12 months. Concomitant neurophysiological changes in the brain indicate (after only 4-8 weeks' treatment) improved vigilance and information processing. In patients with balance disorders, mean improvements of 44-78% in symptom severity and quality of life have been observed with nicergoline. Although clinical experience with nicergoline in vascular disorders is limited to relatively short-term, small-scale studies, it has been successfully used in rehabilitation therapy of patients with chronic ischaemic stroke. Open-label evaluations suggest that nicergoline may also be valuable in glaucoma, depression and peripheral arterio-pathy. Adverse events of nicergoline, if any, are related to the central nervous system, the metabolic system and the overall body. Most are considered typical symptoms of ergot derivatives. Because of their generally mild and transient nature, treatment discontinuations occur relatively infrequently. The efficacy of nicergoline combined with a favourable safety and tolerability profile at commonly applied doses (60 mg/day) make this agent a valuable therapy in patients with mild to moderate dementia, vascular diseases and balance disorders.

Ergotamine and nicergoline - facts and myths.

Ergotamine, being a representative of naturally occurring ergoline alkaloids, derived from d-lysergic acid, and nicergoline, a d-lumilysergic acid derivative belonging to semi-synthetic ergot-derived alkaloids, display diversified affinity for adrenergic, serotoninergic, and dopamine receptors. Although introduction of triptans marginalized use of ergotamine, nicergoline is used in cerebral metabolic-vascular disorders, and dementia. Additionally, nicergoline exhibits a safety profile comparable to that of placebo, and none of the reviewed studies reported any incidence of fibrosis or ergotism with nicergoline treatment. In line with the recent data, activation of 5-HT2B receptor by ergot derivatives i.e. ergotamine, methysergide, pergolide, and carbegoline is involved in pathogenesis of drug-induced valvulopathy. In contrary structurally related drugs - lisuride and terguride do not increase the risk of valvular heart disease. It seems, that more detailed mechanistic studies on nicergoline and ergotamine might be beneficial for determining structural requirements related to activation of G-protein as well as alternative signal transduction pathways e.g. ß-arrestins or different kinases, and responsible for drug liabilities.

Nicergoline in mild to moderate dementia. A multicenter, double-blind, placebo-controlled study.

In view of some controversies still existing about the real efficacy of ergot derivatives in the management of dementia, a double-blind, randomized, parallel group trial extending up to 6 months was carried out to compare the effects of nicergoline, 60 mg daily, and placebo in 315 patients suffering from mild to moderate dementia. Clinical evaluation was performed by the SCAG scale. The trial, which included a 1-month placebo run-in period, showed that both placebo and nicergoline were associated with some degree of improvement. The effect of nicergoline, however, was significantly greater and more sustained, steadily increasing with time. In particular, the difference between nicergoline and placebo in mean total SCAG score was 5.5 at 3 months (95% confidence interval: 3.6-7.4) and increased to 9.8 at 6 months (95% confidence interval: 7.8-11.8). A comparison of nicergoline versus placebo in the frequencies of changes in each item of the SCAG showed also a significant difference at 6 months, the percent of patients displaying an improvement by at least 2 points ranging from 13.5 (bothersome) to 30.2 (disorientation) in nicergoline group, against 4.1 (self-care) to 14.3 (fatigue) in placebo group. The safety of nicergoline, as judged by hemodynamic changes and drug-related adverse reactions, was quite satisfactory.

Nicergorine-induced lichen planus-like eruption.

A case of a lichen planus-like eruption due to nicergorine on the lower legs of an 84-year-old woman is reported. She presented with slightly pruritic, erythematous plaques of six months' duration. She had taken eight kinds of drugs, including nicregorine for cerebral arteriosclerosis, for two years. After nicergorine was discontinued, the eruption gradually disappeared. Readministration of nicergorine induced a similar eruption within two months. Histologic findings were identical in the two biopsy specimens obtained at the first visit and from the recurrent lesion. To our knowledge, this is the first report on nicergorine-induced lichen planus-like eruptions.

[Therapy of organic brain syndrome with nicergoline given once a day]. / Therapie des hirnorganischen Psychosyndroms mit Nicergolin in täglicher Einmalgabe.

In a double-blind, active-controlled study 30 patients with mild to moderate multiinfarct dementia diagnosed according to DSM III definition were treated by either 20 mg nicergoline or 4.5 mg co-dergocrine mesilate once daily during eight weeks. Therapeutic effects on symptoms of the organic brain syndrome were quantitatively measured by standardized psychological and psychometric methods evaluating cognitive and thymopsychic functions. Main criteria, which were tested by inferential analysis, were SCAG total score (Sandoz Clinical Assessment Geriatric Scale), SCAG overall impression and the AD Test (alphabetischer Durchstreichtest). Other results were assessed by descriptive statistics. Both treatments resulted in a statistically significant improvement in most of the tested functions. The effects of 4.5 mg co-dergocrine mesilate s.i.d. were in accordance with published results. Although differing slightly with respect to individual results 20 mg of nicergoline once daily showed the same efficacy on the whole.

[Nicergoline-induced Prinzmetal angina. "Heartache" instead of headache]. / Nicergoline által indukált Prinzmetal-angina. Fejfájás helyett "szívfájás".

A 56 year old woman was admitted to our hospital with crescendo chest pain in the last ten days. Her past history included hypertension treated by 100 mg metoprolol for more than ten years and right carotid endarterectomy. She complained headache and a treatment of 20 mg nicergoline (ergoline derivate) daily was started. Her chest pains started always one hour after the nicergoline intake. The chest pain was accompanied by breathing difficulties and sweating of 5 min duration at first but the next days it lasted longer and longer. Next morning following her admission, one hour after the nicergoline administration she had severe chest pain again. The ECG showed ST-segment elevation in inferior leads resolved after nitroglycerin administration. The angiogram revealed normal coronary artery. Nicergoline was stopped. The patient was treated with felodipine and remains free of symptoms. Nicergoline was good for head but worse for heart in this case.

A systematic review and meta-analysis assessing adverse event profile and tolerability of nicergoline.

OBJECTIVE: To evaluate the safety profile of nicergoline compared with placebo and other active agents from published randomised controlled trials. DESIGN: Systematic review and meta-analysis of nicergoline compared with placebo and other active agents across various indications. DATA SOURCES: MEDLINE, Medline-in-process, Cochrane, EMBASE, EMBASE alerts, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR) and Cochrane Methodology Register (CMR) for all the randomised controlled trials, open-label or blinded, in adults treated with nicergoline. Studies published until August 2013 were included. REVIEW METHOD: 29 studies were included for data extraction. The studies included in this review were majorly from European countries and mostly in cerebrovascular disease (n=15) and dementia (n=8). RESULTS: The treatment withdrawals were comparatively lower in the nicergoline group as compared with the placebo group (RR=0.92; 95% CI 0.7 to 1.21) and other active comparators (RR=0.45; 95% CI 0.10 to 1.95), but the difference was non-significant. Incidence of any adverse events (AEs) was slightly higher (RR=1.05; 95% CI 0.93 to 1.2) while incidence of serious AEs was lower (RR=0.85; 95% CI 0.50 to 1.45) in the nicergoline compared with placebo group. Frequency of anxiety was significantly lower in nicergoline as compared with placebo (p=0.01). Other AEs including diarrhoea, gastric upset, dizziness and drowsiness were less frequent in the nicergoline group when compared with placebo/active drugs, but the difference was non-significant. Frequency of hypotension and hot flushes was slightly higher in the nicergoline group but the difference was non-significant. None of the studies reported any incidence of fibrosis or ergotism with nicergoline treatment. CONCLUSIONS: Nicergoline is an ergot derivative, but its safety profile is better than other ergot derivatives like ergotamine and ergotoxine. This systematic review and meta-analysis suggests that nicergoline has a good safety profile. None of the studies included in this systematic review reported any incidence of fibrosis or ergotism with nicergoline.

Safety of nicergoline as an agent for management of cognitive function disorders.

Nicergoline is a semisynthetic ergot derivative and has a selective alpha-1A adrenergic receptor blocking property and also other additional mechanisms of actions, both in the brain and in the periphery. It is in clinical use for over three decades in over fifty countries for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer's disease and has been found to be beneficial in a variety of other conditions. However, concerns about its safety have been raised, especially after the European medicines agency's (EMEA's) restriction in the use of all ergot derivatives including nicergoline. But, most of the available literature and data suggest that the adverse events with nicergoline are mild and transient. Further, none of the available treatment options for cognitive disorders afford definitive resolution of symptoms. In this backdrop, we discuss the pharmacology of nicergoline with special emphasis on the safety of this compound, especially when used in patients suffering from cognitive function disorders.

[Treatment of arterial hypertension in the elderly with an alpha-blocker: nicergoline (author's transl)]. / Traitement de l'hypertension artérielle du sujet âgé par un alpha-bloquant: la nicergoline.

The tolerance and anti-hypertensive activity of nicergoline, an alpha-adrenoceptor blocking agent, were studied in 28 hypertensive subjects older than 65 years (mean age: 84 years). The trial was conducted double-blind: 14 subjects were given nicergoline 30 mg/day divided into 6 doses ("lyocs"), and 14 subjects received a placebo identical in appearance with the drug. A mean decrease of 34 mm Hg in systolic arterial pressure (p < 0.001) and of 16 mm Hg in diastolic arterial pressure (p < 0.001) was observed in subjects under nicergoline. The corresponding changes in blood pressure (-12 and -7.9 mm Hg respectively) in subjects under placebo were not significant. No side-effect requiring discontinuation of treatment was encountered. The remarkable effectiveness and tolerance of nicergoline make it a highly suitable agent for the treatment of hypertension in elderly people.

A multicenter randomized double-blind study on the efficacy and safety of nicergoline in patients with multi-infarct dementia.

A 6-month double-blind, randomized, placebo-controlled clinical trial preceded by a 3-week single-blind, washout/run-in placebo phase was performed in male and female patients, 55-85 years of age with a clinical diagnosis of mild to moderate multi-infarct dementia according to DSM-III to evaluate the therapeutic efficacy and safety of nicergoline 30 mg b.i.d. Primary endpoints for efficacy were the changes in the Sandoz Clinical Assessment Geriatric Scale (SCAG) and Mini-Mental State Examination (MMSE) scores at the end of the treatment with respect to baseline. Secondary endpoints were Clinical Global Impression, 3 subtests of the Weschsler Adult Intelligence Scale and Blessed A scale for activities of daily living, and all endpoints in 2-month intervals. A total of 252 patients were screened, 136 patients entered the double-blind phase and were evaluated as intent-to-treat (ITT) patients. Fifteen patients were excluded from the efficacy analyses of valid cases (VC) due to protocol violations or because they dropped out of the study prematurely. Confirmatory efficacy analysis after 6 months of treatment revealed superiority of nicergoline treatment with p < 0.01 for both SCAG and MMSE scores (ITT and VC). Subsequent descriptive efficacy analysis resulted in significant differences in favor of nicergoline, in the majority of cases as early as 2 months after start of treatment. Nicergoline was well tolerated and a similar number of adverse events were observed in both the placebo and the nicergoline group.

Acute interstitial nephritis due to nicergoline (Sermion).

We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking nicergoline and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN.

Lichenoid drug eruption following the Blaschko lines.

Eruptions similar to those of lichen planus (LP) are associated with systemic diseases or have been induced by many drugs. Linear lesions as a Koebner effect are frequently found in LP but isolated long, narrow, linear lesions, which may extend the whole length of the limb, are rare though rather more common in childhood. Some cases of zonal or zosteriform LP have been described in the literature. We describe a case of LP with a linear distribution following the Blaschko embryologic lines induced by nicergoline in a 65-year-old woman with a 6-month history of a pruritic eruption of erythematoviolaceous papules on the left breast, trunk and upper limb, with histological features of LP It would be the first case of linear LP associated with drugs.

Brain protection of nicergoline against hypoxia: EEG brain mapping and psychometry.

In a double-blind, placebo-controlled trial human brain function and mental performance as well as the antihypoxidotic properties of nicergoline were studied utilizing blood gas analysis, EEG brain mapping and psychometry. Hypoxic hypoxidosis was experimentally induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (N2) equivalent to 6,000 m altitude, which was inhaled for 23 min under normobaric conditions by 16 healthy volunteers. They received randomized after an adaptation session placebo, 10 mg, 30 mg and 60 mg nicergoline (NIC). Evaluation of blood gases, brain mapping and psychometry was carried out at 0, 2, 4, 6, 8 hrs oral drug administration. Blood gas analysis demonstrated a drop in PO2 from 95 to 35 and 34 mm Hg in the 14 and 23 min of inhalation, respectively. PCO2 decreased too (38 to 34 and 34 mm Hg), while pH increased (7.39 to 7.44 and 7.44). Base excess increased (-0.6 to 0.6 and 0.4) while standard bicarbonate decreased (24.4 to 24.1 and 23.8 mmol/l). Thus, blood gases remained stable between the 14 and 23 min of hypoxia during which time the neurophysiological and behavioral evaluations were carried out. EEG brain mapping exhibited an increase in delta/theta activity mostly over the parietal, temporal and central regions (left more than right), while alpha activity decreased (mostly over the parietal, central, frontal, fronto-temporal and temporo-occipital regions). 30 and 60 mg NIC attenuated this deterioration of vigilance. At the behavioral level, hypoxic hypoxidosis induced a deterioration of the noo- and thymospsyche which was mitigated by NIC. Based on 13 psychometric variables, the hypoxia-induced performance decrement was on the overall (2nd-8th hr) 43% after placebo as compared with pretreatment normoxic values, while only 29, 24 and 31% after 10, 30 and 60 mg nicergoline, respectively. The difference between placebo and the optimal dosage of nicergoline 30 mg reached the level of statistical significance (p less than 0.01, multiple Wilcoxon).

A 24-month, double-blind, placebo-controlled multicentre pilot study of the efficacy and safety of nicergoline 60 mg per day in elderly hypertensive patients with leukoaraiosis.

In this pilot study, 72 non-demented and non-depressive elderly hypertensive patients with evidence of leukoaraiosis on cerebral computed tomography scan (Rezek score: > 16) were randomly assigned to receive either nicergoline 30 mg b.i.d. (n = 36) or a placebo (n = 36) for 24 months. All patients received antihypertensives and their hypertension was controlled under treatment. They were evaluated by nine neuropsychological tests exploring memory, concentration, verbal and motor performances, administered at baseline and at every six-month interval during the study period. At baseline, the two groups were comparable for all demographic and clinical characteristics, including cognitive functions, except for the delayed recall of the Auditory Verbal Learning Test (AVLT), which was better in the placebo group (P = 0.04). Changes in scores over time were compared between the two groups. At the last visit, patients on nicergoline (n = 31) were found to have deteriorated less or to have improved more on test scores than the patients on placebo (n = 30). Significant differences were observed for memory function (AVLT short term recall, P = 0.026; AVLT delayed recall, P = 0.013; and, Benton Visual Retention Test, P = 0.002) and attention and concentration (Letter Cancellation Test, P = 0.043; and, WAIS-R Digit Symbol subtest, P = 0.006). The Rezek score remained unchanged in the two groups. Tolerance of nicergoline was similar to that of placebo. In conclusion, this study shows that nicergoline 30 mg b.i. d. administered over a 24-month period attenuates the deterioration in cognitive functions in elderly hypertensive patients with leukoaraiosis. Whether these effects were specific for this type of white matter changes could not be determined in the context of this pilot study.