Concomitant Bandage Contact Lens, Oral Nicergoline, and Topical Autologous Serum for Severe Neurotrophic Keratitis.

BACKGROUND: To report the outcomes of using the combination of oral nicergoline, autologous serum, and contact lens to enhance corneal epithelization in neurotrophic keratitis and to discuss the clinical potential of this management. METHODS: This was a prospective consecutive case series study of eight patients treated for neurotrophic keratitis at the "Conde de Valenciana" Institute of Ophthalmology. Oral nicergoline, autologous serum, and bandage contact lens were initiated at the same time, immediately after stage 3 diagnosis keratitis was confirmed clinically, and until corneal epithelialization was achieved or eminent corneal perforation was seen. In patients where diabetes was a cause, glycosylate hemoglobin was measured to asses metabolic control. Corneal esthesiometry and corrected distance visual acuity were assessed before and after treatment. RESULTS: This study included eight eyes of eight patients (5 men [62.5%], average age 57±17.9 years). All patients completed at least 1 month of follow-up after nicergoline and contact lens suspension. Of the eight eyes, no one had positive culture growth and complete epithelial healing was achieved in all cases. Half of patients had diabetes and had a poor metabolic control. Corneal sensitivity improved in all eyes almost 2 centimeters in Cochet-Bonnet esthesiometry ( P= 0.01). In addition, final visual acuity gains were obtained ( P= 0.100). CONCLUSIONS: The combination of oral nicergoline, autologous serum, and bandage contact lens simultaneously could be an alternative in the management of stage 3 neurotrophic keratitis when conventional medical treatment has no improvement of corneal epithelization.

[Combined chemoreflexes of the vertebral arteries zone on the systemic arterial pressure, cerebral and infra-aural blood circulation in the experiment]. / Sochetannye khemorefleksy zony pozvonochnykh arterii na sistemnoe arterial'noe davlenie, tserebral'noe i vnutriushnoe krovoobrashchenie v eksperimente.

OBJECTIVE: To study reflexes coming from the chemoreceptors in the humoral-isolated vertebral artery zone on systemic arterial pressure, cerebral and intra-ear hemodynamics in separate stimulation with angioprotectors. RESULTS: A more pronounced reflex depression of the above-described effectors was caused by Nicergoline, it was less pronounced when using Vinpocetine and Pentoxifylline. Correlation analysis in doing so of the dynamics of arterio-venular coefficient of bulbar conjunctiva vessels and the membrane of the ears labyrinth round window revealed a direct relationship. CONCLUSION: These studies objectivize the therapy of ear labyrinth discirculation with angioprotectives.

Role of nicergoline in corneal wound healing in diabetic rats.

BACKGROUND: To investigate the effect of nicergoline on the rate of complete corneal ulcer reepithelialization (CCUR) in diabetic rats with diabetic keratopathy. METHODS: Forty-eight streptozotocin-induced diabetic rats were randomly divided into two groups. The experimental group (n = 24) received nicergoline (10 mg.kg- 1.day- 1), while the control group (n = 24) received a placebo. A corneal epithelial defect was induced using a corneal diamond burr, and defect area was compared at time points of 0, 12, 24, 48 and 72 h after the injury using image analysis software. The probability of CCUR within 72 h was assessed using the Kaplan-Meier survival analysis log-rank test. RESULTS: When compared, 4 of the 24 rats (17%) in the placebo group and 12 of the 24 rats (50%) in the nicergoline group were found to have CCUR within 72 h (log-rank = 0.027). Cox regression analysis found no effect of the covariates blood glucose (P = 0.601) or weight (P = 0.322) on the corneal reepithelialization (survival) curve. CONCLUSIONS: Nicergoline increased wound healing rates relative to placebo and may therefore be investigated as a treatment option in diabetic keratopathy.

Nerve growth factor in dogs: Assessment of two immunoassays and selected ocular parameters following a nicergoline challenge per os.

Impairment of corneal nerves can result in the development of ocular surface diseases such as aqueous tear deficiency and neurotrophic keratopathy. This study investigates oral nicergoline, an α-adrenoceptor antagonist shown to enhance endogenous secretion of nerve growth factor (NGF) by the lacrimal gland, as a potential therapy for these conditions. Five female spayed Beagle dogs received a 2-week course of oral nicergoline (10 mg twice daily). Drug safety was evaluated with ophthalmic and physical examinations, blood pressure monitoring, bloodwork, and urinalysis. The effect of nicergoline on the ocular surface was assessed with corneal esthesiometry, Schirmer tear test-1, and tear film breakup time. Drug effect on NGF levels was assessed by collecting tears and blood at baseline and completion of therapy using a bead-based immunoassay and an enzyme-linked immunosorbent assay. Although nicergoline was well tolerated in all dogs, it did not have a significant impact on corneal sensitivity, tear production, or tear stability. Of note, NGF was below the limit of quantification in all tear samples and was only detected in 8/20 serum samples with no significant difference between levels at baseline (189.4 ± 145.1 pg/mL) and completion of therapy (149.4 ± 79.4 pg/mL). Further validation of NGF analytical assays is warranted before nicergoline is investigated in clinical patients.

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.

Dihydrogen Bond in the Aminoborane Complex of a Nicergoline Intermediate.

An aminoborane side product from the nicergoline manufacture process was identified by single-crystal X-ray diffraction. As boranes of pharmaceutical molecules are quite rare, the binding potential of the BH3 group was investigated and compared with similar compounds using Cambridge Structural Database (CSD). Surprisingly, the packing was stabilized by a dihydrogen bond, which triggered a false alert for too-short contact of hydrogen atoms in IUCR checkCIF. As the dihydrogen bond concept is not widely known, such an alert might mislead crystallographers to force -CH3 optimal geometry to -BH3 groups. The B-H distances equal to or less than 1.0 Å (17% of the CSD structures) are substantially biased when analyzing the structures of aminoborane complexes in CSD. To conduct proper searching, B-H bond length normalization should be applied in the CSD search.

The Impact of Efflux Pump Inhibitors on the Activity of Selected Non-Antibiotic Medicinal Products against Gram-Negative Bacteria.

The potential role of non-antibiotic medicinal products in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated. It is highly likely that the presence of efflux pumps may be one of the reasons for the weak activity of non-antibiotics, as in the case of some non-steroidal anti-inflammatory drugs (NSAIDs), against Gram-negative rods. The activity of eight drugs of potential non-antibiotic activity, active substance standards, and relevant medicinal products were analysed with and without of efflux pump inhibitors against 180 strains of five Gram-negative rod species by minimum inhibitory concentration (MIC) value determination in the presence of 1 mM MgSO4. Furthermore, the influence of non-antibiotics on the susceptibility of clinical strains to quinolones with or without PAßN (Phe-Arg-ß-naphthylamide) was investigated. The impacts of PAßN on the susceptibility of bacteria to non-antibiotics suggests that amitriptyline, alendronate, nicergoline, and ticlopidine are substrates of efflux pumps in Gram-negative rods. Amitriptyline/Amitriptylinum showed the highest direct antibacterial activity, with MICs ranging 100-800 mg/L against all studied species. Significant decreases in the MIC values of other active substances (acyclovir, atorvastatin, and famotidine) tested with pump inhibitors were not observed. The investigated non-antibiotic medicinal products did not alter the MICs of quinolones in the absence and in the presence of PAßN to the studied clinical strains of five groups of species.

[The use nicergoline in the treatment of diabetes mellitus]. / Ispol'zovanie nitsergolina v terapii oslozhnenii sakharnogo diabeta.

Presented herein is a literature review aimed at investigating the appropriateness and possibility of using nicergoline (sermion) for treatment of patients suffering from diabetes mellitus. The analysis includes the most clinically significant results of scientific studies. The material to be reviewed was retrieved using the following key words: 'nicergoline', 'sermion', and 'diabetes mellitus' (with their respective Russian equivalents) in such databases as Medline, PubMed, ScienceDirect, PMC, Cochrane, as well as archives of both Russian and foreign journals, guidelines (clinical guidelines on rendering medical care for patients with diabetes mellitus, selected lectures on endocrinology). A broad spectrum of action and no significant side effects have made it possible to use this drug in various pathological conditions. At the same time, because of limited experience of using nicergoline for vascular diseases and an insufficient number of the carried out studies the precise role of this therapeutic agent in clinical practice has not yet been conclusively defined. Special attention is given to the analysis of efficacy of nicergoline in atherosclerosis and diabetes mellitus.

Microwave-assisted digestion using nitric acid for heavy metals and sulfated ash testing in active pharmaceutical ingredients.

The monitoring of inorganic impurities in active pharmaceutical ingredients plays a crucial role in the quality control of the pharmaceutical production. The heavy metals and residue on ignition/sulfated ash methods employing microwave-assisted digestion with concentrated nitric acid have been demonstrated as alternatives to inappropriate compendial methods recommended in United States Pharmacopoeia (USP) and European Pharmacopoeia (Ph. Eur.). The recoveries using the heavy metals method ranged between 89% and 122% for nearly all USP and Ph. Eur. restricted elements as well as the recoveries of sodium sulfate spikes were around 100% in all tested matrices. The proposed microwave-assisted digestion method allowed simultaneous decomposition of 15 different active pharmaceutical ingredients with sample weigh up to 1 g. The heavy metals and sulfated ash procedures were successfully applied to the determination of heavy metals and residue on ignition/sulfated ash content in mycophenolate mofetil, nicergoline and silymarin.

[Identification of related substances in nicergoline by HPLC-MS].

To study the related substances in nicergoline, electrospray positive ionization high resolution TOF/MS was used for the determination of the accurate mass and elemental composition of the related substances. Triple quadrupoles tandem MS/MS was employed for the determination of the fragmentations of the parent ions. 16 related substances were detected and identified to be eight synthetic by-products and eight degradation products, by using impurity references matching, product mass spectra fragmentations elucidation, and verified further according to synthetic processes and stress testing results. The results obtained are valuable for nicergoline manufacturing process control and quality assurance.

pH-driven colloidal transformations based on the vasoactive drug nicergoline.

The structure of colloidal self-assembled drug delivery systems can be influenced by intermolecular interactions between drug and amphiphilic molecules, and is important to understand in the context of designing improved delivery systems. Controlling these structures can enable controlled or targeted release systems for poorly water-soluble drugs. Here we present the interaction of the hydrophobic vasoactive drug nicergoline with the internal structure of nanostructured emulsion particles based on the monoglyceride-water system. Addition of this drug leads to modification of the internal bicontinuous cubic structure to generate highly pH-responsive systems. The colloidal structures were characterized with small-angle X-ray scattering and visualized using cryogenic transmission electron microscopy. Reversible transformations to inverse micelles at high pH, vesicles at low pH, and the modification of the spacing of the bicontinuous cubic structure at intermediate pH were observed, and enabled the in situ determination of an apparent pKa for the drug in this system--a difficult task using solution-based approaches. The characterization of this phase behavior is also highly interesting for the design of pH-responsive controlled release systems for poorly water-soluble drug molecules.

Effect of four different size reduction methods on the particle size, solubility enhancement and physical stability of nicergoline nanocrystals.

Nicergoline, a poorly soluble active pharmaceutical ingredient, possesses vaso-active properties which causes peripheral and central vasodilatation. In this study, nanocrystals of nicergoline were prepared in an aqueous solution of polysorbate 80 (nanosuspension) by using four different laboratory scale size reduction techniques: high pressure homogenization (HPH), bead milling (BM) and combination techniques (high pressure homogenization followed by bead milling HPH + BM, and bead milling followed by high pressure homogenization BM + HPH). Nanocrystals were investigated regarding to their mean particles size, zeta potential and particle dissolution. A short term physical stability study on nanocrystals stored at three different temperatures (4, 20 and 40 °C) was performed to evaluate the tendency to change in particle size, aggregation and zeta potential. The size reduction technique and the process parameters like milling time, number of homogenization cycles and pressure greatly affected the size of nanocrystals. Among the techniques used, the combination techniques showed superior and consistent particle size reduction compared to the other two methods, HPH + BM and BM + HPH giving nanocrystals of a mean particle size of 260 and 353 nm, respectively. The particle dissolution was increased for any nanocrystals samples, but it was particularly increased by HPH and combination techniques. Independently to the production method, nicergoline nanocrystals showed slight increase in particle size over the time, but remained below 500 nm at 20 °C and refrigeration conditions.

Wakayama symposium: new therapies for modulation of epithelialization in corneal wound healing.

Many factors are involved in the corneal wound healing mechanism, including adhesion, migration, and proliferation of corneal epithelial cells. Abnormal corneal wound healing leads to corneal edema, neovascularization, scar formation, and poor vision. Three agents, 17ß-estradiol, nicergoline, and ß-glucan, have demonstrated positive effects on the wound healing response in laboratory experiments and may be of help in controlling wound healing in corneas that have suffered epithelial damage or have undergone refractive surgery.

Silencing brassinosteroid receptor BRI1 impairs herbivory-elicited accumulation of jasmonic acid-isoleucine and diterpene glycosides, but not jasmonic acid and trypsin proteinase inhibitors in Nicotiana attenuata.

The brassinosteroid (BR) receptor, BR insensitive 1 (BRI1), plays a critical role in plant development, but whether BRI1-mediated BR signaling is involved in plant defense responses to herbivores was largely unknown. Here, we examined the function of BRI1 in the resistance of Nicotiana attenuata (Solanaceae) to its specialist insect herbivore Manduca sexta. Jasmonic acid (JA) and JA-isoleucine conjugate (JA-Ile) are important hormones that mediate resistance to herbivores and we found that after wounding or simulated herbivory NaBRI1 had little effect on JA levels, but was important for the induction of JA-Ile. Further experiments revealed that decreased JAR (the enzyme for JA-Ile production) activity and availability of Ile in NaBRI1-silenced plants were likely responsible for the low JA-Ile levels. Consistently, M. sexta larvae gained more weight on NaBRI1-silenced plants than on the control plants. Quantification of insect feeding-induced secondary metabolites revealed that silencing NaBRI1 resulted in decreased levels of carbon-rich defensive secondary metabolites (hydroxygeranyllinalool diterpene glycosides, chlorogenic acid, and rutin), but had little effect on the nitrogen-rich ones (nicotine and trypsin proteinase inhibitors). Thus, NaBRI1-mediated BR signaling is likely involved in plant defense responses to M. sexta, including maintaining JA-Ile levels and the accumulation of several carbon-rich defensive secondary metabolites.

[Study of the effect of Unifuzol on cognitive impairment and damage to the hippocampus and cerebral cortex during course administration to rats with bilateral stenosis of the common carotid arteries, causing chronic circulatory failure]. / Vliyanie preparata Unifuzol na sostoyanie kognitivnykh funktsii v usloviyakh eksperimental'nogo khronicheskogo narusheniya mozgovogo krovoobrashcheniya.

OBJECTIVE: To study the effect of Unifuzol (L-arginine sodium succinate) on cognitive impairment, cerebral blood flow, and damage to the tissues of the hippocampus and cerebral cortex during a 10-day course of administration to rats with chronic cerebral ischemia (CCI) caused by bilateral stenosis of the common carotid arteries (CCA). MATERIAL AND METHODS: The study was conducted on male rats with CCI caused by bilateral stenosis of the CCA by 60%. 40 days after surgery, rats received Unifusol (21, 42 and 84 ml/kg), nicergoline (10 mg/kg), citicoline (500 mg/kg) or placebo (0.9% NaCl) for 10 days. Next, cognitive impairments were assessed in the Morris Water Maze and the New Object Recognition (NOR) test, as well as the level of motor and exploratory activity in the Open Field test. The level of cerebral blood flow was determined immediately after the CCA stenosis and at the end of the experiment. Animals were euthanized in a CO2 incubator, after which the brain was removed and subjected to morphometric analysis. RESULTS: In animals that were modeled with CCA stenosis, pronounced behavioral and cognitive impairments occurred as a result of a decrease in blood flow in the vessels of the brain and subsequent changes in the tissues of the hippocampus and the cerebral cortex. Intravenous course administration of Unifuzol at doses of 42 and 84 ml/kg to animals with CCI was comparable in efficiency to nicergoline and citicoline, which was expressed in greater preservation of the cognitive abilities of animals in the Morris Water Maze and NOR tests. In the Open Field test, animals injected with Unifusol at doses of 42 and 84 ml/kg performed more acts of motor and exploratory activity than animals from the placebo group, and had a higher level of cerebral blood flow (compared to animals that were injected with citicoline). Based on the results of a morphological study, it was found that the most significant neuroprotective effect was provided by nicergoline and Unifuzol (at doses of 42 and 84 ml/kg). CONCLUSION: Unifuzol at a course of administration at doses of 42 and 84 ml/kg, comparable to the reference drugs nicergoline and citicoline, reduces the severity of psychoneurological deficit in animals with CCI, comparable to them improves the microcirculation of brain tissues, preventing damage to brain tissues.

[Serum level of S100B as a marker of progression of vascular mild cognitive impairment into subcortical vascular dementia and therapy effectiveness].

We evaluated serum level of S100B in 11 patients with subcortical vascular dementia (SVD) and 19 patients with subcortical vascular mild cognitive impairment (SVMCI). Comparable groups were age-matched (79.18 +/- 7.76 in SVD group, 77.84 +/- 3.83 in SVMCI; P = 0.53). 22 patients were assessed after 1 month therapy. It was shown that the serum S100B level significantly increased--(0.065 +/- 0.020) micro/l (P = 0.0005) in SVD patients comparing to SVMCI ones - (0.043 +/- 0.010) microg/l. S100B level was significantly correlated with the clinical parameters: MMSE performance (r(s) = -0.61), CDR (r(s) = 0.58), attention task (r(s) = -0.46), pseudobulbar syndrome severity (r(s) = 0.37) and walking alteration (r(s)= 0.37). In patients with reduction of S100B level due to therapy (positive dynamics, n = 12) we registered significant improvement of some clinical parameters: MMSE, attention level, walking. In patients with increasing of S100B level (negative dynamics, n = 10) we didn't registered improvement of any clinical parameters. We made the conclusion that the serum level of S100B could be used as marker of progression SVMCI into SVD and therapy effectiveness.

Use of Nicergoline as Adjunctive Treatment of Neurotrophic Keratitis in Routine Clinical Practice: A Case Series.

PURPOSE: To describe the effectiveness and safety of nicergoline in patients with epithelial corneal defect or corneal ulcer due to neurotrophic keratitis (NK). METHODS: A prospective case series review was performed in 14 patients with NK who started treatment with nicergoline as an off-label prescription from January to November 2020. Patients with a epithelial defect or corneal ulcer due to NK were treated with oral nicergoline. RESULTS/SERIAL CASES: Complete corneal healing was observed in 10 (71.4%) of the 14 patients after 25.6 ± 26.60 days (range 7-90) with nicergoline. In three (21.5%) patients wound healing was not achieved, and one patient (7.1%) was lost to follow-up. The mean time between diagnosis and the starting of nicergoline was 10.92 ± 8.85 days (0-28). No adverse effects of nicergoline were observed. CONCLUSION: Nicergoline as an adjunctive treatment for NK showed a potential use in the healing of epithelial defect in real-life clinical practice.

[Vascular cognitive impairment]. / Sosudistye kognitivnye narusheniya.

Vascular cognitive impairment is considered the second most common cause of dementia after Alzheimer's disease. One of the most significant factors leading to vascular dementia is stroke, which increases the risk of developing dementia by about 2 times. Delayed-onset post-stroke dementia is mainly due to severe small vessel disease, recurrent stroke, or concomitant Alzheimer's disease. Among the many mechanisms involved in the development of vascular cognitive impairment, cerebral small vessel disease is perhaps the most common, contributing to cognitive impairment independent of stroke. An important feature of small vessel disease is its steady progression. The cognitive decline in cerebrovascular disease, including small vessel disease, is also usually gradual and gradual, progresses slowly, and the underlying defect extends to processing speed, complex attention, and fronto-executive functions. Vascular cognitive impairments are quite heterogeneous in nature, while having a negative impact on all major cognitive domains. Patient management should include the earliest possible diagnosis of cognitive impairment and the appointment of timely therapy. One of the drugs that has been successfully used to treat vascular cognitive impairment is nicergoline (Sermion). The clinical efficacy of the drug is achieved due to the improvement of cerebral blood flow, a positive effect on cholinergic neurotransmission and neuroprotective action.

The effects of intrathecal nicergoline and nimodipine in cerebral vasospasm: an experimental study in rabbits.

BACKGROUND: the aim of this study was to assess and to compare the ability of intrathecal nicergoline and nimodipine in prevention of cerebral vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). METHOD: twenty male New Zealand white rabbits were allocated into four groups randomly. Subarachnoid hemorrhage was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: (1) control [no SAH (n = 5)], (2) SAH only (n = 5), (3) SAH plus nimodipine (n = 5), and (4) SAH plus nicergoline (n = 5). FINDINGS: there was a statistically significant difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements of the control and SAH-only groups (p < 0.05). Basilar artery vessel diameter and luminal section areas in group 3 were significantly higher than in group 2 (p < 0.05). Basilar artery vessel diameter and basilar artery luminal section areas in group 4 were significantly higher than in group 2 (p < 0.05). There was no significant difference between basilar artery vessel diameter and basilar artery luminal section areas in group 3 and group 4. CONCLUSIONS: these findings demonstrate that intrathecal nicergoline has a vasodilatatory effect in an experimental model of SAH in rabbits but not more than that of nimodipine.

New therapeutic approaches in the treatment of diabetic keratopathy: a review.

The cornea is densely innervated, and the integrity of these nerve fibres is critical in maintaining the refractive and protective functions of the cornea. Many ocular and systemic diseases can adversely affect corneal sensory nerves and consequently impair their function, with vision loss being the inevitable consequence of severe corneal neurotrophic ulceration. However, current standard treatments regimens are often ineffective. Over the past three decades, the role of growth factors in maintaining the normal structure and function of the cornea, and in corneal epithelial healing, has become increasingly evident. Many preclinical and clinical trials have shown that growth factors and cytokines can significantly enhance epithelialization (epithelial proliferation and migration) and consequently accelerate wound healing. More recently, local/topical administration of insulin, naltrexone (opioid antagonist) and nicergoline (ergoline derivatives) were found to improve, and significantly increase, the corneal wound healing rate. This report reviews the major attributes of these growth factors and therapeutic agents that may be used in ameliorating impaired corneal wound healing, and presents a perspective on the potential clinical use of these agents as a new generation of ophthalmic pharmaceuticals for the treatment of diabetic keratopathy.