Integrative assessment of the effectiveness and safety of outpatient use of Picamilon

Close metadata

OBJECTIVE

To study the efficacy and safety of the use of the drug Picamilon with various therapy regimens in patients with stage I of chronic cerebral ischemia (CCI).

MATERIAL AND METHODS

Material and methods. An open randomized comparative clinical trial included 44 patients with stage CCI aged 46 to 67 years (average age 55.6±6.76 years). Patients were randomized into two groups, patients of group 1 (n=23) received Picamilon orally in tablets of 50 mg 3 times/day for 60 days; group 2 (n=21) received Picamilon first parenterally at 100 mg i/m for 10 days, then in tablets of 50 mg 3 times/day for 50 days. The total duration of therapy was 60 days. The study included 4 visits (before treatment, 10 days later, 60 days later, 1.5 months after completion of treatment). The dynamics of cognitive status were assessed according to the Montreal Cognitive Function Assessment Scale (MoCA), vegetative disorders on the A.M. Wayne scale, neurological disorders on the A.I. Fedin scale, and sleep quality on the Ya.I. Levin scale. The study of the state of cerebral blood flow (dopplerography of intracranial vessels) and endothelial function (assessment of the level of methylation.

RESULTS

During treatment, in the total sample of patients, there was a positive trend in the results of the MoCA scale, increasing in the delayed period (24.9/26.5/28.3 points, p=0.022 and p<0.001); improvement in sleep quality in 50% of patients by visit 3 and in 84% by visit 4, in the 2nd group the effect occurred in 28% of patients, in the 1st — in 11%, by the end of the study the effect was comparable (p=0.508). Improvement according to Fedin A.I. scale noted in 77% of patients, values decreased from 11.9±8.3 to 6±6.1 points (p<0.0001) and to 2.77±4.43 points by visit 4 (p<0.0001). Normalization of autonomic functions was observed in 29% of patients (p=0.024) without intergroup differences. Picamilon therapy showed high efficacy in terms of clinical outcomes (up to 89%), good tolerability (98% of patients) and a favorable safety profile (less than 8.6% of AEs). The use of Picamilon was accompanied by an increase in the linear velocity of blood flow, a decrease in the thickness of the intima-media complex and the resistance index; a decrease in elevated ADMA concentrations and ADMA/MMA and (ADMA+SDMA)/MMA ratios.

CONCLUSION

The use of Picamilon is effective in patients with stage I CCI, contributes to a significant regression of neurological deficits, cognitive impairment, improved sleep quality and autonomic function; improves vascular endothelial function, reduces the risk of atherosclerosis and cardiovascular complications in patients. The optimal duration of therapy with Picamilon in stage I of chronic cerebral ischemia is 2 months.

Keywords:

chronic cerebral ischemia

cognitive impairment

cerebrovascular diseases

neurometabolic therapy

Picamilon

Authors:

Danilov A.B.

Sechenov First Moscow State Medical University (Sechenov University)

ORCID: 0000-0001-8904-2538

Shindryaeva N.N.

Sechenov First Moscow State Medical University (Sechenovsky University)

ORCID: 0000-0001-6560-2756

Borodulina I.V.

Russian Medical Academy of Continuing Postgraduate Education

SPIN RSCI: 2152-5737
ORCID: 0000-0001-7526-1553

Lunegov T.D.

Khromsistemslab LLC

ORCID: 0000-0002-7020-9446

Received:

18.06.2024

Accepted:

02.07.2024

List of references:

Zaharov VV, Vahnina NV, Gromova DO, Tarapovskaya AV. Hronicheskaya nedostatochnost’ mozgovogo krovoobrashcheniya: opisanie klinicheskogo sluchaya. Therapeutic Archive. 2016;88(4):93-99. (In Russ.). https://doi.org/10.17116/terarkh201688493-99
Klocheva EG, Aleksandrov MV, Panina EB. Cerebrovaskulyarnye zabolevaniya. Golovnaya bol’: uchebnoe posobie. CHast’ I. SPb.: Izdatel’stvo SZGMU im. I.I. Mechnikova; 2014. (In Russ.).
Nevrologiya. Nacional’noe rukovodstvo. Kratkoe izdanie. Red. E.I. Guseva, A.N. Konovalova, A.B. Gekht. M.: GEOTAR-Media; 2018. (In Russ.).
Shishkova VN, Adasheva TV. Hronicheskaya ishemiya golovnogo mozga i golovnaya bol’ u pacientov v praktike terapevta. Nevrologiya, Nejropsihiatriya, Psihosomatika. 2021;13(1):131-137. (In Russ.). https://doi.org/10.14412/2074-2711-2021-1-131-137
Artem’ev DV, Zaharov VV, Levin OS, et al. Starenie i nejrodegenerativnye rasstrojstva: kognitivnye i dvigatel’nye narusheniya v pozhilom vozraste. Pod red. H.H. YAhno. M.: Servier; 2005. (In Russ.).
Kulesh AA, Emelin AYU, Bogolepova AN, et al. Klinicheskie proyavleniya i voprosy diagnostiki hronicheskogo cerebrovaskulyarnogo zabolevaniya (hronicheskoj ishemii golovnogo mozga) na rannej (dodementnoj) stadii. Nevrologiya, Nejropsihiatriya, Psihosomatika. 2021;13(1):4-12. (In Russ.).
Zaharov VV, Slepcova KB, Martynova OO. Hronicheskaya ishemiya mozga: vzglyad iz HKHI veka. RMZH. 2021;5:45-49. (In Russ.).
Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689-701. https://doi.org/10.1016/S1474-4422(10)70104-6
Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12(5):483-497. https://doi.org/10.1016/S1474-4422(13)70060-7
Vermeer SE, William T, Longstreth WT, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol. 2007;6:611-619. https://doi.org/10.1016/S1474-4422(07)70170-9
Kovács KR, Czuriga D, Bereczki D, et al. Silent Brain Infarction — A Review of Recent Observations. Int J Stroke. 2013;8(5):334-347. https://doi.org/10.1111/j.1747-4949.2012.00851.x
Cannistraro RC, Badi M, Eidelman BH, et al. CNS small vessel disease. A clinical review. Neurology. 2019;92:1146-1156. https://doi.org/10.1212/WNL.0000000000007654
Suslina ZA, Varakin YuYa. Klinicheskoe rukovodstvo po rannej diagnostike, lecheniyu i profilaktike sosudistyh zabolevanij golovnogo mozga. 2-e izd. M.: MEDpress-inform; 2017. (In Russ.).
Higashi Y, Kihara Y, Noma K. Endothelial dysfunction and hypertension in aging. Hypertension Research. 2012;35:1039-1047.
Hassan A, Markus HS. Genetics and ischaemic stroke. Brain. 2000;123:1784-1812.
Fateeva VV, Vorob’eva OV. The correlation between endothelial dysfunction and depressive disorder in middle-aged patients with hypertension-associated microangiopathy. 4th European Stroke Organisation Conference (Gothenburg, Sweden 2018) AS23-028.
Gao Q, Fan Y, Mu LY, et al. S100B and ADMA in cerebral small vessel disease and cognitive dysfunction. J Neurol Sci. 2015;354(1-2):27-32. https://doi.org/10.1016/j.jns.2015.04.031
Rodionov RN, Blohin IO, Galagudza MM, et al. Asimmetrichnyj dimetilarginin i ego rol’ v etiologii i patogeneze serdechno-sosudistyh zabolevanij. Arterial’naya Gipertenziya. 2008;14(4):306-314. (In Russ.). https://doi.org/10.18705/1607-419X-2008-14-4-306-314
Baum C, Johannsen SS, Zeller T, et al. Gutenberg Health Study investigators. ADMA and arginine derivatives in relation to non-invasive vascular function in the general population. Atherosclerosis. 2016;244:149-156. https://doi.org/10.1016/j.atherosclerosis.2015.10.101
Bahls M, Friedrich N, Atzler D, et al. L-Arginine and SDMA Serum Concentrations Are Associated with Subclinical Atherosclerosis in the Study of Health in Pomerania (SHIP). PLoS One. 2015;10(6):e0131293. https://doi.org/10.1371/journal.pone.0131293
Willeit P, Freitag DF, Laukkanen JA, et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. J Am Heart Assoc. 2015;4(6):e001833. https://doi.org/10.1161/JAHA.115.001833
Levin OS. Discirkulyatornaya encefalopatiya: sovremennye predstavleniya o mekhanizmah razvitiya i lechenii. Consilium Medicum. 2006;8:2-7. (In Russ.).
Gusev EH, Skvorcova VN. Ishemiya golovnogo mozga. M.: Medicina; 2000. (In Russ.).
Damulin NV. Discirkulyatornaya encefalopatiya: patogenez, klinika, lechenie: Metodicheskie rekomendacii. M. 2005. (In Russ.).
Bogolepova AN. Sosudistaya depressiya i kognitivnaya disfunkciya. Nevrologiya, Nejropsihiatriya, Psihosomatika. 2019;11(3):26-31. (In Russ.).
Vejn AM. Vegetativnye rasstrojstva. Klinika, diagnostika, lechenie. M.: MHA; 1998. (In Russ.).
Klinicheskie rekomendacii «Ishemicheskij insul’t i tranzitornaya ishemicheskaya ataka u vzroslyh» Ministerstvo zdravoohraneniya RF. 2020. (In Russ.).
Suslina ZA, Rumyanceva SA. Nejrometabolicheskaya terapiya hronicheskoj ishemii mozga. M.: VUNMC MZ RF; 2005. (In Russ.).
Zakusov VV, Kaverina NV, Bendikov EA. Avtorskoe svidetel’stvo №1393428 Vazoaktivnoe i neotropnoe sredstvo «pikamilon». (In Russ.).
Mitrohin KV, Baranishin AA. Klassifikaciya i kratkoe opisanie lekarstvennyh preparatov — analogov proizvodnyh gamma-aminomaslyanoj kisloty i toksicheskih veshchestv, vliyayushchih na GAMK-ergicheskuyu svyaz’. Russian Journal of Anesthesiology and Reanimatology. 2018; 6: 22-30. (In Russ.). https://doi.org/10.17116/anaesthesiology201806122
Perfilova VN, Borodkina LE. Uchastie gamma-aminomaslyanokislotno-ergicheskoj sistemy v regulyacii mozgovogo krovoobrashcheniya. Vestnik Rossijskoj Voenno-Medicinskoj Akademii. 2014;1(45):203-211. (In Russ.).
Perfilova VN, Tyurenkov IN, Ostrovskij OV, et al. Korrekciya disfunkcii mitohondrij GAMK-ergicheskimi sredstvami. Volgogradskij Nauchno-Medicinskij Zhurnal. 2010;3:10. (In Russ.).
Silkina IV, Gan’shina TS, Seredenin SB, Mirzoyan RS. GAMK-ergicheskij mekhanizm cerebrovaskulyarnogo i nejroprotektornogo effektov afobazola i pikamilona. Eksperimental’naya i Klinicheskaya Farmakologiya. 2005;1(68):20-24. (In Russ.).
Perfilova VN, Tyurenkov IN, Grechko OYU. Vliyanie strukturnogo analoga gamma-aminomaslyanoj kisloty na vyrazhennost’ processov perekisnogo okisleniya lipidov i aktivnost’ antioksidantnyh fermentov v usloviyah ishemicheskogo povrezhdeniya miokarda. Vestnik Volgogradskogo Gosudarstvennogo Medicinskogo Universiteta. 2010;1:33. (In Russ.).
Mirzoyan RS, Gan’shina TS, Kim GA, et al. Translyacionnyj potencial eksperimental’noj farmakologii cerebrovaskulyarnyh rasstrojstv. Annaly Klinicheskoj i Eksperimental’noj Nevrologii. 2019;13(3):34-40. (In Russ.). https://doi.org/10.25692/ACEN.2019.3.5
Green AR, Hainsworth AH, Jackson DM. GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke. Neuropharmacology. 2000;39(9):1483-1494. https://doi.org/10.1016/s0028-3908(99)00233-6
Matsumoto N, Kumamoto E, Furue H, Yoshimura M. GABA-mediated inhibition of glutamate release during ischemia in substantia gelatinosa of the adult rat. J Neurophysiol. 2003;89(1):257-264. https://doi.org/10.1152/jn.00384.2002
Lihodeeva VA, Spasov AA, Isupov IB, Mandrikov VB. Vliyanie pikamilona na parametry cerebral’nogo krovotoka dizadaptirovannyh plovcov s raznymi tipami sistemnoj gemodinamiki. Vestnik Novyh Medicinskih Tekhnologij. 2011;18(1):150-153. (In Russ.).
Ershov IN, Luchkina EV, Pokrovskij MV, Pokrovskaya TG. Issledovanie endotelio- i kardioprotektivnyh effektov lamotridzhina, pikamilona i val’proatov pri eksperimental’noj endotelial’noj disfunkcii. Kubanskij Nauchnyj Medicinskij Vestnik. 2009;3(108):50-53. (In Russ.).
Suslina ZA, Geraskina LA, Fonyakin AV. Arterial’naya gipertoniya, sosudistaya patologiya mozga i antigipertenzivnoe lechenie. M.: ZAO «Mediagafiks»; 2006. (In Russ.).
Gan’shina TS, Kurdyumov IN, Maslennikov DV. Effektivnost’ pikamilona pri sochetannoj sosudistoj patologii golovnogo mozga i serdca. Eksperimental’naya i Klinicheskaya Farmakologiya. 2022;85(1):3-6. (In Russ.).
Tykhonenko T, Guzyk M, Tykhomyrov A, et al. Modulatory effects of vitamin B3 and its derivative on the levels of apoptotic and vascular regulators and cytoskeletal proteins in diabetic rat brain as signs of neuroprotection. Biochim Biophys Acta Gen Subj. 2022;1866(11):1302-1307. https://doi.org/10.1016/j.bbagen.2022.130207
Instrukciya po medicinskomu primeneniyu preparata Pikamilon. (In Russ.). https://grls.rosminzdrav.ru/
Shtok V.N. Farmakoterapiya v nevrologii: Prakticheskoe rukovodstvo. 4-e izd. M.: MNA; 2006;115-179. (In Russ.).
Gusev EI, CHukanova EI, CHukanova AS. Hronicheskaya cerebrovaskulyarnaya nedostatochnost’ (faktory riska, patogenez, klinika, lechenie). M. 2018. (In Russ.).
Latysheva VYA, Galinovskaya NV, Shaporova OV, et al. Lechenie bol’nyh s discirkulyatornoj encefalopatiej. Recept. 2008;3(59):69-75. (In Russ.).
Saharov VYu, Skripnik YuV. Primenenie pikamilona v vosstanovitel’nom lechenii u postinsul’tnyh pacientov s emocional’no-kognitivnymi narusheniyami. Davidenkovskie chteniya. Nevrologiya. SPb.: Sankt-Peterburgskaya obshchestvennaya organizaciya «Chelovek i ego zdorov’e»; 2021. (In Russ.).
Kostenko EV, Kashezhev AG, Petrova LV, Eneeva MA. Medikamentoznoe soprovozhdenie reabilitacii pacientov, perenesshih insul’t: rol’ GAMK-ergicheskih preparatov. Medicinskij Sovet. 2023;17(21):80-91. (In Russ.). https://doi.org/10.21518/ms2023-408
Spravochnik po formulirovaniyu klinicheskogo diagnoza boleznej nervnoj sistemy. Pod red. V.N. Shtoka, O.S. Levina. M.: MNA; 2006. (In Russ.).
Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment. J Am Ger Soc. 2005;53(4):695-699.
Vejn AM. Vegetativnye rasstrojstva. Klinika, lechenie, diagnostika. Rukovodstvo. MIA. 2010. (In Russ.).
Levin YaI, Eligulashvili TS, Posohov SI, et al. Farmakoterapiya insomnij: rol’ Imovana. Rasstrojstva sna. Pod red. Yu.A. Aleksandrovskogo, A.M. Vejna. SPb.: Medicinskoe informacionnoe agentstvo; 1995. (In Russ.).
Fedin AI. Diagnostika i lechenie hronicheskoj ishemii mozga. Consilium Medicum. 2016;18(2):8-12. (In Russ.).
Arlouskaya Y. Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA) Concentrations in Patients with Obesity and the Risk of Obstructive Sleep Apnea. J Clin Med. 2019;8(6):897.
Böger R H., Zoccali C. ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atherosclerosis Supp. 2003;4(4):23-28.
Bouras G. Asymmetric dimethylarginine (ADMA): a promising biomarker for cardiovascular disease? Curr Top Med Chem. 2013;13(2):180-200.
Lajer M. Plasma concentration of asymmetric dimethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care. 2008;31(4):747-752.
Sibal L. The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev. 2010;6(2):82-90.
Kalueff A, Nutt DJ. Role of GABA in memory and anxiety. Depress Anxiety. 1996-1997;4(3):100-110.
Landim MBP, Casella Filho A, Chagas ACP. Asymmetric dimethylarginine (ADMA) and endothelial dysfunction: implications for atherogenesis. Clinics. 2009;64(5):471-478.

Close metadata