Pathogenetic therapy of cognitive impairment: results of a multicenter placebo-controlled clinical trial of the efficacy and safety of Miladean

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OBJECTIVE

Evaluation of the efficacy and safety of the use of the drug Miladean in the treatment of patients with cognitive disorders (CDs) of vascular genesis.

MATERIAL AND METHODS

In during the double-blind multicenter prospective randomized placebo-controlled phase III clinical trial, 300 patients with CDs and chronic cerebral ischemia were randomized into 3 groups: group 1 (n=100) received Miladean (daily dose: memantine 10 mg + melatonin 6 mg), group 2 (n=101) — memantine (10 mg/day), group 3 — placebo (n=99) for 8 weeks. The dynamics of the overall score (the primary criterion of effectiveness) and the proportion of patients with improvement on the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), the dynamics of visual-spatial orientation disorders (Benton test), sleep quality (Pittsburgh Sleep Quality Index scale) and the safety of therapy were evaluated.

RESULTS

Miladean demonstrated efficacy in the treatment of CDs: a statistically and clinically significant decrease in the overall score on the ADAS-Sod scale was shown (by 6.1 versus 4.7 and 3.5 points in the 2nd (p=0.009) and 3rd (p<0.05) groups) and an increase in the proportion of patients (96.9%) with clinically and statistically a significant improvement compared to the 2nd and 3rd groups (p=0.019 and p<0.001 respectively). Miladean significantly improved the performance in the Benton test (1.20±1.66 vs. 0.64±1.69 points in group 3, p=0.026) and sleep quality (84.7% of patients with CDs), compared to placebo (63.9%) and memantine (64.3%) (p=0.002 in both cases). Miladean was well tolerated, there were no cases of interaction with basic therapy drugs.

CONCLUSION

The combination of many different pathogenetic effects of Miladean suggests that it has the ability to slow down the rate of progression of CDs and stabilize the condition of patients. The unique combination of active substances in Miladean has been proven to be effective and safe in the treatment of patients with CDs.

Keywords:

Miladean

cognitive impairment

mild cognitive impairment

sleep disturbance

neuroinflammation

Authors:

Levin O.S.

Russian Medical Academy of Continuous Professional Education

SPIN RSCI: 5342-1373
Scopus AuthorID: 57147160800
ORCID: 0000-0003-3872-5923

Zaharov V.V.

Sechenov First Moscow State Medical University (Sechenov University)

ORCID: 0000-0002-8447-3264

Khacheva K.K.

Valenta Pharm

ORCID: 0000-0001-9441-4797

Vladykin A.L.

Valenta Pharm

ORCID: 0000-0003-2511-2992

Globenko A.A.

Valenta Pharm JSC

ORCID: 0000-0001-9295-2663

Received:

21.09.2023

Accepted:

22.09.2023

List of references:

Morley JE. An overview of cognitive impairment. Clin Geriat Med. 2018;34(4):505-513.
Salthouse TA. When does age-related cognitive decline begin? Neurobiol Aging. 2009;30(4):507-514.
Deary I. Age-associated cognitive decline. Br Med Bul. 2009;92(1):135-152.
Zakharov VV. Prevalence and treatment of cognitive disorders in a neurological clinic. The results of the All-Russian PROMETHEUS study. Consilium Medicum. 2008;10(2):114-117. (In Russ.).
Geda YE, Roberts RO, Knopman DS. Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. Arch Gen Psychiatry. 2008;65(10):1193-1198.
Qin J, He Z, Wu L, et al. Prevalence of mild cognitive impairment in patients with hypertension: a systematic review and meta-analysis. Hypertens Res. 2021;44(10):1251-1260. https://doi.org/10.1038/s41440-021-00704-3
Illarioshkin SN. Early (pre-dement) forms of cognitive disorders. Consilium Medicum. 2007;9(2):107-111. (In Russ.).
Yakhno NN, Preobrazhenskaya IS, Zakharov VV, et al. Prevalence of cognitive impairments in neurological diseases: Analysis of the activities of a specialized outpatient reception office. Neurology, Neuropsychiatry, Psychosomatics. 2012;4(2):30-35. (In Russ.).
Tian Z, Ji X, Liu J. Neuroinflammation in Vascular Cognitive Impairment and Dementia: Current Evidence, Advances, and Prospects. Int J Mol Sci. 2022;23(11):6224.
Zuo W, Wu J. The interaction and pathogenesis between cognitive impairment and common cardiovascular diseases in the elderly. Ther Adv Chron Dis. 2022;13(6):20406223211063020.
Parfenov VA, Ostroumova TM, Ostroumova OD, et al. Vascular cognitive impairment: pathophysiological mechanisms, insights into structural basis, and perspectives in specific treatments. Neuropsychiatric Disease and Treatment. 2019;14:1381-1402.
Kokhan VS. Glutamate/GABA imbalance in the comparative analysis of radiation and traumatic lesions of the cerebral cortex. Aerospace and Environmental Medicine. 2019;53(6):5-10. (In Russ.).
Agrawal S, Schneider JA. Vascular pathology and pathogenesis of cognitive impairment and dementia in older adults. Cerebral Circulation-Cognition and Behavior. 2022;3:100-108.
Sachdev PS. The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients. Neurology. 2004;62(6):912-919.
Zakharov VV, Yakhno NN, Reyhart DV, et al. Combination of memantine and melatonin in moderate cognitive impairment in old age: possible clinical prospects. Neurological Journal. 2013;18(6):40-48. (In Russ.).
Transm JN. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm. 1994;43(6):91-104.
Meisner F, Scheller C, Kneitz S, et al. Memantine upregulates BDNF and prevents dopamine deficits in SIV-infected macaques: a novel pharmacological action of memantine. Neuropsychopharmacol. 2008;33(9):2228-2236. https://doi.org/10.1038/sj.npp.1301615
Lv X, Li Q, Mao S, The protective effects of memantine against inflammation and impairment of endothelial tube formation induced by oxygen-glucose deprivation/reperfusion. Aging (Albany NY). 2020;12(21):21469-21480. https://doi.org/10.18632/aging.103914
Willenborg B, Schmoller A, Caspary J, et al. Memantine prevents hypoglycemia-induced decrements of the cerebral energy status in healthy subjects. J Clin Endocrinol Metab. 2011;96(2):384-388. https://doi.org/10.1210/jc.2010-1348
Mayo JC. Melatonin and Parkinson’s disease. Endocrine. 2005;27(6):169-178.
Permpoonputtana K, Mukda S, Govitrapong P. Effect of melatonin on D-amphetamine-induced neuroglial alterations in postnatal rat hippocampus and prefrontal cortex. Neurosci Lett. 2012;524(1):1-4.
Wang F, Zou Z, Gong Y, et al. Regulation of human brain microvascular endothelial cell adhesion and barrier functions by memantine. J Mol Neurosci. 2017;62(5):123-129. https://doi.org/10.1007/s12031-017-0917-x
Madsen BK, Zetner D, Møller AM, et al. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database Syst Rev. 2020;12(12):CD009861. https://doi.org/10.1002/14651858.CD009861.pub3
An open comparative study of the safety and pharmacokinetic parameters of the drug Miladian, tablets dispersed in the oral cavity containing 5 mg of memantine and 3 mg of melatonin (produced by JSC «Valenta Pharm», Russia), Acatinol Memantine, film-coated tablets (a set of tablets 5 mg, 10 mg, 15 mg, 20 mg) (produced by Merz Pharma GmbH and Co. KGaA, Germany), and Melaxen, film-coated tablets, 3 mg (produced by UNIFARM, Inc., USA), in healthy volunteers. (In Russ.). https://grlsbase.ru/clinicaltrails/clintrail/3292
A prospective multicenter, randomized, double-blind, placebo-controlled study in parallel groups to evaluate the efficacy, safety and tolerability of the combined drug Miladian, tablets dispersed in the oral cavity containing 5 mg of memantine and 3 mg of melatonin, when used in various dosages in patients with mild and moderate cognitive impairment syndrome on background of chronic cerebral ischemia. (In Russ.). https://grlsbase.ru/clinicaltrails/clintrail/952
Benton AL, Varney NR, Hamsher KS. Visuospatial judgment: A clinical test. Arch Neurol. 1978;35(6):364-367.
R Core Team: A language and environment for statistical computing. R Foundation for Statistical Computing. 2018. Vienna, Austria. https://www.r-project.org
Areosa SA, Sherriff F, McShane R. Memantine for dementia. The Cochrane Database Syst Rev. 2005;3:CD003154-CD003154.
Abe M. Association between Benton Visual Retention Test Scores and PET Imaging in Elderly Adults. Cur Alz Res. 2021;18(11):900-907.
Vasey C, McBride J, Penta K. Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin. Nutrients. 2021;13(10):3480.
Blackman J, Swirski M, Clynes J, et al. Pharmacological and non-pharmacological interventions to enhance sleep in mild cognitive impairment and mild Alzheimer’s disease: A systematic review. J Sleep Res. 2021;30(4):e13229.
Park JW, Kim KA, Park JY. Effect of memantine on QT/QTc interval in a healthy Korean population. Clin Pharm Drug Dev. 2021;10(10):1209-1215.

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