Bromantane

Last updated

Bromantane
Bromantane structure.svg
Bromantane ball-and-stick model.png
Clinical data
Trade names Ladasten
Other namesBromantan; Bromontan; ADK-709; N-(2-Adamantyl)-4-bromoaniline; N-(2-Adamantyl)-N-(4-Bromophenyl)amine; N-(4-Bromophenyl)-2-adamantanamine
Routes of
administration
By mouth
ATC code
  • None
Legal status
Legal status
  • US:Unscheduled,not FDA approved
  • Rx-only (RU)
Pharmacokinetic data
Bioavailability 27.5%[ citation needed ]
Onset of action 1.5–2 hours (PO)
Elimination half-life 11.21 hours (in humans), [1]
7 hours (in rats) [2]
Duration of action 8–12 hours (PO)
Identifiers
  • N-(4-Bromophenyl)adamantan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.213.907 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H20BrN
Molar mass 306.247 g·mol−1
3D model (JSmol)
  • C1C2CC3CC1CC(C2)C3NC4=CC=C(C=C4)Br
  • InChI=1S/C16H20BrN/c17-14-1-3-15(4-2-14)18-16-12-6-10-5-11(8-12)9-13(16)7-10/h1-4,10-13,16,18H,5-9H2 X mark.svgN
  • Key:LWJALJDRFBXHKX-UHFFFAOYSA-N X mark.svgN
   (verify)

Bromantane, sold under the brand name Ladasten, is an atypical central nervous system (CNS) stimulant and anxiolytic drug of the adamantane family that is related to amantadine and memantine. Medically, it is approved in Russia for the treatment of neurasthenia. Although the effects of bromantane have been determined to be dependent on the dopaminergic and possibly serotonergic neurotransmitter systems, its exact mechanism of action is unknown, [3] [4] and is distinct in its properties relative to typical stimulants such as amphetamine. Bromantane has sometimes been described as an actoprotector (synthetic adaptogen). [5] [6]

Contents

Effects

Clinical research

The therapeutic effects of bromantane in asthenia are said to onset within 1–3 days. [7] It has been proposed that the combination of stimulant and anxiolytic activity may give bromantane special efficacy in the treatment of asthenia. [8]

In a large-scale, multi-center clinical trial of 728 patients diagnosed with asthenia in Russia, bromantane was given for 28 days at a daily dose of 50 mg or 100 mg. [7] The study concluded with an impression score of 76.0% on the CGI-S and 90.8% on the CGI-I for bromantane, indicating that it is broadly applicable and highly effective. [7] The therapeutic benefit against asthenia was observed to still be present one month after discontinuation of the drug. [7] 3% of patients experienced side effects; though none were considered serious; and 0.8% of patients discontinued treatment due to side effects. [7] Bromantane was also noted to normalize the sleep-wake cycle. [7]

Psychotropic effects

Bromantane is described primarily as a mild stimulant [9] and anxiolytic. [8] It is also said to possess anti-asthenic properties. [10] [8] Bromantane is reported to improve physical and mental performance, hence it could be considered a performance-enhancing drug. [10]

Bromantane has been found to lower the levels of pro-inflammatory cytokines IL-6, IL-17 and IL-4 and to normalize behavior in animal models of depression, and may possess clinical efficacy as an antidepressant. [11] [12] [13] It has also been found to increase sexual receptivity and proceptivity in rats of both sexes, which was attributed to its dopaminergic actions. [14] It has been proposed that bromantane may suppress prolactin levels by virtue of its dopaminergic properties as well. [15] Bromantane has been found to "agonize" amphetamine-induced stereotypies in vivo, suggesting that it might potentiate certain effects of other stimulants. [4]

The stimulant effects of bromantane onset gradually within 1.5–2 hours and last for 8–12 hours when taken orally. [9]

Pharmacology

Pharmacodynamics

Dopamine synthesis enhancement

Although it is frequently labeled as a stimulant, bromantane is distinct in its pharmacology and effects relative to typical stimulants, such as the phenethylamines (e.g., amphetamine and its derivatives) and their structural analogues (e.g., methylphenidate, cocaine, mesocarb, etc.). [16] [17] Whereas the latter directly act on the dopamine transporter (DAT) to inhibit the reuptake and/or induce the release of dopamine, bromantane instead acts via indirect genomic mechanisms to produce a rapid, pronounced, and long-lasting upregulation in a variety of brain regions of the expression of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD) (also known as DOPA decarboxylase), key enzymes in the dopamine biosynthesis pathway. [9] [18] [19] For instance, a single dose of bromantane produces a 2–2.5 fold increase in TH expression in the rat hypothalamus 1.5–2 hours post-administration. [20] The biosynthesis and release of dopamine subsequently increase in close correlation with TH and AAAD upregulation. [9] [18] [19] Enhancement of dopaminergic neurotransmission is observed in the hypothalamus, striatum, ventral tegmental area, nucleus accumbens, and other regions. [9] [18] [19] As such, the key mechanism of the pharmacological activity and psychostimulant effects of bromantane is activation of the de novo synthesis of dopamine via modulation of gene expression. [18]

A selection of quoted excerpts from the medical literature detail the differences between bromantane and typical stimulants: [10] [9] [16]

  • "Bromantane [does] not concede well-known psychostimulant of phenylalkylamine structure and its analogs (amphetamine, [mesocarb], [methylphenidate], etc.) by specific activity. In contrast, bromantane has neither addictive potential nor reveals redundant and exhausting activation of sympaticoadrenergic system, or decelerates the restoring of work capacity at preventive application before forthcoming activity in complicated conditions (hypoxia, high environmental temperature, physical overfatigue, emotional stress, etc.). Bromantane has no prohypoxic activity."
  • "The use of the drug, in contrast to the action of a typical psychostimulant, is not associated with the phenomenon of hyperstimulation and causes no consequences such as functional exhaustion of the body."
  • "Bromantane administration in therapeutic doses is characterized by the almost full absence of side effects including manifestations of withdrawal syndrome and hyperstimulation."
  • "[Bromantane] has low peripheral sympathomimetic effects. Moreover, no signs of [bromantane] dependence and withdrawal symptoms were found."

Bromantane is well tolerated and elicits few side effects (including peripheral sympathomimetic effects and hyperstimulation), does not appear to produce tolerance or dependence, has not been associated with withdrawal symptoms upon discontinuation, and displays an absence of addiction potential, contrary to typical stimulants. [10] [8] In accordance with human findings, animals exposed to bromantane for extended periods of time do not appear to develop tolerance or dependence. [21]

The precise direct molecular mechanism of action by which bromantane ultimately acts as a dopamine synthesis enhancer is unknown. [3] [4] However, it has been determined that activation of certain cAMP-, Ca2+-, and phospholipid-dependent protein kinases such as protein kinase A and especially protein kinase C corresponds with the manifestation of the pharmacological effects of bromantane. [17] [22] Bromantane may activate intracellular signaling cascades by some mechanism (e.g., agonizing some as-yet-undetermined receptor) to in turn activate protein kinases, which in turn cause increased transcription of TH and AAAD. [17] [22]

The related drugs amantadine and memantine also have many properties similar to those of bromantane. [23] [24] [25]

Researchers discovered that amantadine and memantine bind to and act as agonists of the σ1 receptor (Ki = 7.44 μM and 2.60 μM, respectively) and that activation of the σ1 receptor is involved in the central dopaminergic effects of amantadine at therapeutically relevant concentrations; the authors of the study stated that this could also be the mechanism of action of bromantane, as it is in the same family of structurally related compounds and evidence suggests a role of dopamine in its effects. But this could also be seen as evidence of the contrary since bromantane has effects that are distinctly different from amantadine and memantine.

Monoamine reuptake inhibition

Bromantane was once thought to act as a reuptake inhibitor of serotonin and dopamine. [3] [16] [26] While bromantane can inhibit the reuptake of serotonin, dopamine, and to a lesser extent norepinephrine in vitro in rat brain tissue, the concentrations required to do so are extremely high (50–500 μM) and likely not clinically relevant. [16] [26] Although one study found an IC50 for dopamine transport of 3.56 μM, relative to 28.66 nM for mesocarb; neither drug affected serotonin transport at the tested concentrations, in contrast. [27] The lack of typical stimulant-like effects and adverse effects seen with bromantane may help corroborate the notion that it is not acting significantly as a monoamine reuptake inhibitor, but rather via a different mechanism.

Other actions

Bromantane has been found to increase the expression of neurotrophins including brain-derived neurotrophic factor and nerve growth factor in certain rat brain areas. [28]

Although not relevant at clinical dosages, bromantane has been found to produce anticholinergic effects, including both antimuscarinic and antinicotinic actions, at very high doses in animals, and these effects are responsible for its toxicity (that is, LD50) in animals. [26] [29] [30] [31]

Pharmacokinetics

Bromantane is used clinically in doses of 50 mg to 100 mg per day in the treatment of asthenia. [7]

The main metabolite of bromantane is 6β-hydroxybromantane. [32]

Chemistry

Bromantane is an adamantane derivative. It is also known as adamantylbromphenylamine, from which its name was derived. [1]

Closely related adamantanes with similar effects include adapromine, amantadine, chlodantane, gludantane (gludantan), memantine, and rimantadine. [23]

Synthesis

Patents: 57%: Bromantane synthesis.svg
Patents: 57%:

The reductive amination between Adamantanone [700-58-3] and 4-Bromoaniline [106-40-1] in the presence of formic acid gave bromantane (3).

History

In the 1960s, the adamantane derivative amantadine (1-aminoadamantane) was developed as an antiviral drug for the treatment of influenza. [36] Other adamantane antivirals subsequently followed, such as rimantadine (1-(1-aminoethyl)adamantane) and adapromine (1-(1-aminopropyl)adamantane). [5] [36] It was serendipitously discovered in 1969 that amantadine possesses central dopaminergic stimulant-like properties, [37] [38] and subsequent investigation revealed that rimantadine and adapromine also possess such properties. [39] Amantadine was then developed and introduced for the treatment of Parkinson's disease due to its ability to increase dopamine levels in the brain. [37] It has also notably since been used to help alleviate fatigue in multiple sclerosis. [40]

With the knowledge of the dopaminergic stimulant effects of the adamantane derivatives, bromantane, which is 2-(4-bromophenylamino) adamantane, was developed in the 1980s at the Zakusov State Institute of Pharmacology, USSR Academy of Medical Sciences (now the Russian Academy of Medical Sciences) in Moscow as "a drug having psychoactivating and adaptogen properties under complicated conditions (hypoxia, high environmental temperature, physical overfatigue, emotional stress, etc.)". [10] [4] It was found to produce more marked and prolonged stimulant effects than the other adamantanes, [41] and eventually entered use. [10] The drug was notably given to soldiers in the Soviet and Russian militaries to "shorten recovery times after strong physical exertion". [10] After the break-up of the Soviet Union in 1991, bromantane continued to be researched and characterized but was mainly limited in use to sports medicine (for instance, to enhance athletic performance). [10] In 1996, it was encountered as a doping agent in the 1996 Summer Olympics when several Russian athletes tested positive for it, and was subsequently placed on the World Anti-Doping Agency banned list in 1997 as a stimulant and masking agent. [10] [42]

Bromantane was eventually repurposed in 2005 as a treatment for neurasthenia. [43] It demonstrated effectiveness and safety for the treatment of the condition in extensive, large-scale clinical trials, [7] and was approved for this indication in Russia under the brand name Ladasten sometime around 2009. [8]

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Amantadine</span> Medication used to treat dyskinesia

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It is also used for a variety of other uses. The drug is taken by mouth.

<span class="mw-page-title-main">Phenylpiracetam</span> Chemical compound

Phenylpiracetam, is a phenyl-substituted analog of the drug piracetam. It was developed in 1983 as a medication for Soviet Cosmonauts to treat the prolonged stresses of working in space. Phenylpiracetam was created at the Russian Academy of Sciences Institute of Biomedical Problems in an effort led by psychopharmacologist Valentina Ivanovna Akhapkina. In Russia it is now available as a prescription drug. Research on animals has indicated that phenylpiracetam may have anti-amnesic, antidepressant, anticonvulsant, anxiolytic, and memory enhancement effects.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Punding</span> Compulsive performance of repetitive, mechanical tasks

Punding is compulsive performance of repetitive, mechanical tasks, such as assembling and disassembling, collecting, or sorting objects. It can also apply to digital objects, such as computer files and data. The term was originally coined to describe complex, prolonged, purposeless, and stereotyped behaviour in phenmetrazine and chronic amphetamine users, by Swedish forensic psychiatrist G. Rylander, in 1968. It was later described in Parkinson's disease, but mainly in cases of patients being treated with dopaminergic drugs. It has also been described in methamphetamine and cocaine users, as well as in some patients with gambling addictions, and hypersexuality.

<span class="mw-page-title-main">Gidazepam</span> Benzodiazepine medication

Gidazepam, also known as hydazepam or hidazepam, is a drug which is an atypical benzodiazepine derivative, developed in the Soviet Union. It is a selectively anxiolytic benzodiazepine. It also has therapeutic value in the management of certain cardiovascular disorders.

<span class="mw-page-title-main">Mesocarb</span> Stimulant drug

Mesocarb is a drug that is currently being developed for Parkinson's disease.

<span class="mw-page-title-main">Latrepirdine</span> Antihistamine drug

Latrepirdine is an antihistamine drug which has been used clinically in Russia since 1983.

<span class="mw-page-title-main">SB-242084</span> Chemical compound

SB-242084 is a psychoactive drug and research chemical which acts as a selective antagonist for the 5HT2C receptor. It has anxiolytic effects, and enhances dopamine signalling in the limbic system, as well as having complex effects on the dopamine release produced by cocaine, increasing it in some brain regions but reducing it in others. It has been shown to increase the effectiveness of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants, and may also reduce their side effects. In animal studies, SB-242084 produced stimulant-type activity and reinforcing effects, somewhat similar to but much weaker than cocaine or amphetamines.

<span class="mw-page-title-main">Amfonelic acid</span> Chemical compound

Amfonelic acid is a research chemical and dopaminergic stimulant with antibiotic properties. Limited clinical trials have been conducted, and it is primarily used in scientific research.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain. No selective and robust DRAs are currently known. On the other hand, many releasing agents of both dopamine and norepinephrine and of serotonin, norepinephrine, and dopamine are known. Serotonin–dopamine releasing agents (SDRAs), for instance 5-chloro-αMT, are much more rare and are not selective for dopamine release but have also been developed. Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. Selective DRAs, as well as NDRAs, have medical applications in the treatment of attention deficit hyperactivity disorder (ADHD).

<i>N</i>-Phenylacetyl-<small>L</small>-prolylglycine ethyl ester Prodrug

N-Phenylacetyl-l-prolylglycine ethyl ester is promoted as a nootropic and is a prodrug of cyclic glycine-proline. Other names include the brand name Noopept, developmental code GVS-111, and proposed INN omberacetam.

<span class="mw-page-title-main">Fabomotizole</span> Anxiolytic drug

Fabomotizole is an anxiolytic drug launched in Russia in the early 2000s. It produces anxiolytic and neuroprotective effects without any sedative or muscle relaxant actions. Its mechanism of action remains poorly defined however, with GABAergic, NGF- and BDNF-release-promoting, MT1 receptor agonism, MT3 receptor antagonism, and sigma agonism suggested as potential mechanisms. Fabomotizole was shown to inhibit MAO-A reversibly and there might be also some involvement with serotonin receptors. Clinical trials have shown fabomotizole to be well tolerated and reasonably effective for the treatment of anxiety.

<span class="mw-page-title-main">Selank</span> Chemical compound

Selank is a nootropic, anxiolytic peptide based drug developed by the Institute of Molecular Genetics of the Russian Academy of Sciences. Selank is a heptapeptide with the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro (TKPRPGP). It is a synthetic analogue of human tuftsin.

<span class="mw-page-title-main">Emoxypine</span> Chemical compound

Emoxypine (2-ethyl-6-methyl-3-hydroxypyridine), also known as Mexidol or Mexifin, a succinate salt, is chemical compound which is claimed by its manufacturer, the Russian company Pharmasoft Pharmaceuticals, to have antioxidant and actoprotector properties,, but these purported properties of emoxypine have not been proven. Its chemical structure resembles that of pyridoxine (a type of vitamin B6).

<span class="mw-page-title-main">Nooglutyl</span> Chemical compound

Nooglutyl is a nootropic agent that was studied at the Research Institute of Pharmacology, Russian Academy of Medical Sciences as a potential treatment for amnesia.

<span class="mw-page-title-main">Adapromine</span> Chemical compound

Adapromine is an antiviral drug of the adamantane group related to amantadine (1-aminoadamantane), rimantadine, and memantine (1-amino-3,5-dimethyladamantane) that is marketed in Russia for the treatment and prevention of influenza. It is an alkyl analogue of rimantadine and is similar to rimantadine in its antiviral activity but possesses a broader spectrum of action, being effective against influenza viruses of both type A and B. Strains of type A influenza virus with resistance to adapromine and rimantadine and the related drug deitiforine were encountered in Mongolia and the Soviet Union in the 1980s.

<span class="mw-page-title-main">Tolibut</span> Chemical compound

Tolibut, also known as 3-(p-tolyl)-4-aminobutyric acid (or β-(4-methylphenyl)-GABA), is drug that was developed in Russia. It is an analogue of γ-aminobutyric acid (GABA) and is the 4-methyl analogue of phenibut, and is also an analogue of baclofen where the 4-chloro substitution has been replaced with a 4-methyl substitution. Tolibut has been described as possessing analgesic, tranquilizing, and neuroprotective properties. It is not fully clear as to whether the drug was ever approved or used medically in Russia.

Actoprotectors or synthetic adaptogens are compounds that enhance an organism's resilience to physical stress without increasing heat output. Actoprotectors are distinct from other performance-enhancing substances in that they increase physical and psychological resilience via non-exhaustive action. The term "actoprotector" is used to describe synthetic and isolated compounds possessing adaptogenic properties. By contrast, the term "adaptogen" is most often use to describe a natural herb as a whole, which can contain hundreds if not thousands of biologically active components.

<span class="mw-page-title-main">Chlodantane</span> Adaptogen drug that was never marketed

Chlodantane (developmental code name ADK-910) is a drug described as an adaptogen or actoprotector "of the estrogen activity type" that was developed in Russia and was never marketed. It is an adamantane derivative and is closely related to bromantane (N-(2-adamantyl)-N-(para-bromophenyl)amine) and other adamantanes. It has been said to improve physical performance. However, only animal or cell culture research has been conducted and it has not been studied in humans. The drug is described as having a broader spectrum of activity than bromantane. It also has immunostimulant effects that are said to be more pronounced than those of bromantane.

References

  1. 1 2 "Ladasten (adamantylbromphenylamine) Tablets for Oral Use. Full Prescribing Information". Russian State Register of Medicines (in Russian). Lekko CJSC. p. 1. Archived from the original on 3 February 2016. Retrieved 27 January 2016.
  2. Neild PJ, Gazzard BG (September 1997). "HIV-1 infection in China". Lancet. 350 (9082): 963. doi: 10.1016/S0140-6736(05)63309-0 . PMID   9314899. S2CID   40317188.
  3. 1 2 3 Grekhova TV, Gainetdinov RR, Sotnikova TD, Krasnykh LM, Kudrin VS, Sergeeva SA, et al. (1995). "Effect of bromantane, a new immunostimulating agent with psychostimulating activity, on the release and metabolism of dopamine in the striatum of freely moving rats. A microdialysis study". Bulletin of Experimental Biology and Medicine. 119 (3): 294–296. doi:10.1007/BF02445840. ISSN   0007-4888. S2CID   33214442.
  4. 1 2 3 4 Iezhitsa IN, Spasov AA, Bugaeva LI (2001). "Effects of bromantan on offspring maturation and development of reflexes". Neurotoxicology and Teratology. 23 (2): 213–222. doi:10.1016/S0892-0362(01)00119-2. PMID   11348840.
  5. 1 2 Spasov AA, Khamidova TV, Bugaeva LI, Morozov IS (2000). "Adamantane derivatives: Pharmacological and toxicological properties (review)". Pharmaceutical Chemistry Journal. 34 (1): 1–7. doi:10.1007/BF02524549. ISSN   0091-150X. S2CID   41620120.
  6. Morozov IS, Ivanova IA, Lukicheva TA (2001). "Actoprotector and Adaptogen Properties of Adamantane Derivatives (A Review)". Pharmaceutical Chemistry Journal. 35 (5): 235–238. doi:10.1023/A:1011905302667. ISSN   0091-150X. S2CID   29475883.
  7. 1 2 3 4 5 6 7 8 Voznesenskaia TG, Fokina NM, Iakhno NN (2010). "[Treatment of asthenic disorders in patients with psychoautonomic syndrome: results of a multicenter study on efficacy and safety of ladasten]". Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova (in Russian). 110 (5 Pt 1): 17–26. PMID   21322821.
  8. 1 2 3 4 5 Neznamov GG, Siuniakov SA, Teleshova SE, Chumakov DV, Reutova MA, Siuniakov TS, et al. (2009). "[Ladasten, the new drug with psychostimulant and anxiolytic actions in treatment of neurasthenia (results of the comparative clinical study with placebo)]". Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova (in Russian). 109 (5): 20–26. PMID   19491814.
  9. 1 2 3 4 5 6 Mikhaylova M, Vakhitova JV, Yamidanov RS, Salimgareeva MK, Seredenin SB, Behnisch T (October 2007). "The effects of ladasten on dopaminergic neurotransmission and hippocampal synaptic plasticity in rats". Neuropharmacology. 53 (5): 601–608. doi:10.1016/j.neuropharm.2007.07.001. PMID   17854844. S2CID   43661752.
  10. 1 2 3 4 5 6 7 8 9 Oliynyk S, Oh S (September 2012). "The pharmacology of actoprotectors: practical application for improvement of mental and physical performance". Biomolecules & Therapeutics. 20 (5): 446–456. doi:10.4062/biomolther.2012.20.5.446. PMC   3762282 . PMID   24009833.
  11. Tallerova AV, Kovalenko LP, Durnev AD, Seredenin SB (2011). "[Effect of antiasthenic drug ladasten on the level of cytokines and behavior in experimental model of anxious depression in C57BL/6 male mice]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 74 (11): 3–5. PMID   22288152.
  12. Tallerova AV, Kovalenko LP, Durnev AD, Seredenin SB (November 2011). "Effect of ladasten on the content of cytokine markers of inflammation and behavior of mice with experimental depression-like syndrome". Bulletin of Experimental Biology and Medicine. 152 (1): 58–60. doi:10.1007/s10517-011-1453-2. PMID   22803040. S2CID   23634912.
  13. Tallerova AV, Kovalenko LP, Kuznetsova OS, Durnev AD, Seredenin SB (January 2014). "Correcting effect of ladasten on variations in the subpopulation composition of T lymphocytes in C57BL/6 mice on the experimental model of an anxious-depressive state". Bulletin of Experimental Biology and Medicine. 156 (3): 335–337. doi:10.1007/s10517-014-2343-1. PMID   24771370. S2CID   13007622.
  14. Kuzubova EA, Bugaeva LI, Spasov AA (2004). "[The effect of bromantan on the sexual behavior and conception in rats]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 67 (3): 34–37. PMID   15341065.
  15. Iëzhitsa IN, Bugaeva LI, Spasov AA, Morozov IS (1999). "[The effect of the actoprotector preparation bromantane on the postnatal development of rat pups]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 62 (6): 39–44. PMID   10650526.
  16. 1 2 3 4 Iezhitsa IN, Spasov AA, Bugaeva LI (2001). "Effects of bromantan on offspring maturation and development of reflexes". Neurotoxicology and Teratology. 23 (2): 213–222. doi:10.1016/s0892-0362(01)00119-2. PMID   11348840.
  17. 1 2 3 Vakhitova YV, Yamidanov RS, Vakhitov VA, Seredenin SB (2005). "cDNA macroarray analysis of gene expression changes in rat brain after a single administration of a 2-aminoadamantane derivative". Molecular Biology. 39 (2): 244–252. doi:10.1007/s11008-005-0035-7. ISSN   0026-8933. S2CID   39459723.
  18. 1 2 3 4 Vakhitova I, Iamidanov RS, Seredinin SB (2004). "[Ladasten induces the expression of genes regulating dopamine biosynthesis in various structures of rat brain]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 67 (4): 7–11. PMID   15500036.
  19. 1 2 3 Vakhitova YV, Yamidanov RS, Vakhitov VA, Seredenin SB (2005). "The effect of ladasten on gene expression in the rat brain". Doklady. Biochemistry and Biophysics. 401 (1–6): 150–153. doi:10.1007/s10628-005-0057-z. PMID   15999825. S2CID   28048257.
  20. Vakhitova I, Sadovnikov SV, Iamidanov RS, Seredenin SB (July 2006). "[Cytosine demethylation in the tyrosine hydroxylase gene promoter in the hypothalamus cells of the rat brain under the action of an aminoadamantane derivative Ladasten]". Genetika (in Russian). 42 (7): 968–975. PMID   16915929.
  21. Iëzhitsa IN, Bugaeva LI, Spasov AA, Morozov IS (2000). "[Effect of bromantane on the rat neurologic status in two month course]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 63 (5): 13–17. PMID   11109517.
  22. 1 2 Vakhitova I, Salimgareeva MK, Seredenin SB (2004). "[Effect of ladasten on the proteinase C activity in the rat brain cells]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 67 (2): 12–15. PMID   15188752.
  23. 1 2 Morozov IS, Ivanova IA, Lukicheva TA (2001). "[Actoprotector and adaptogen properties of adamantane derivatives (a review)". Pharmaceutical Chemistry Journal. 35 (5): 235–238. doi:10.1023/A:1011905302667.
  24. Danysz W, Dekundy A, Scheschonka A, Riederer P (February 2021). "Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials". J Neural Transm (Vienna). 128 (2): 127–169. doi:10.1007/s00702-021-02306-2. PMC   7901515 . PMID   33624170.
  25. Huber TJ, Dietrich DE, Emrich HM (March 1999). "Possible use of amantadine in depression". Pharmacopsychiatry. 32 (2): 47–55. doi:10.1055/s-2007-979191. PMID   10333162.
  26. 1 2 3 Morozov IS, Pukhova GS, Avdulov NA, Sergeeva SA, Spasov AA, Iezhitsa IN (1999). "[The mechanisms of the neurotropic action of bromantan]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 62 (1): 11–14. PMID   10198757.
  27. Zimin IA, Abaimov DA, Budygin EA, Zolotarev I, Kovalev GI (February 2010). "[Role of the brain dopaminergic and serotoninergic systems in psychopharmacological effects of ladasten and sydnocarb]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 73 (2): 2–5. PMID   20369592.
  28. Salimgareeva MK, Yamidanov RS, Vakhitova YV, Seredenin SB (January 2012). "Mechanisms of action of ladasten: activation of gene expression for neurotrophins and mitogen-activated kinases". Bulletin of Experimental Biology and Medicine. 152 (3): 313–317. doi:10.1007/s10517-012-1516-z. PMID   22803074. S2CID   15466533.
  29. Bugaeva LI, Verovskiĭ VE, Iezhitsa IN, Spasov AA (2000). "[An acute toxicity study of bromantane]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 63 (1): 57–61. PMID   10763112.
  30. Iezhitsa IN, Spasov AA, Bugaeva LI, Morozov IS (April 2002). "Toxic effect of single treatment with bromantane on neurological status of experimental animals". Bulletin of Experimental Biology and Medicine. 133 (4): 380–383. doi:10.1023/a:1016206306875. PMID   12124651. S2CID   3050185.
  31. Iezhitsa IN, Spasov AA, Bugaeva LI, Morozov IS (April 2002). "Toxic effect of single treatment with bromantane on neurological status of experimental animals". Bulletin of Experimental Biology and Medicine. 133 (4): 380–383. doi:10.1023/A:1016206306875. PMID   12124651. S2CID   3050185.
  32. Athanasiadou I, Angelis YS, Lyris E, Vonaparti A, Thomaidis NS, Koupparis MA, et al. (January 2012). "Two-step derivatization procedures for the ionization enhancement of anabolic steroids in LC-ESI-MS for doping control analysis". Bioanalysis. 4 (2): 167–175. doi:10.4155/bio.11.308. PMID   22250799.
  33. RU 1601978,Klimova NV, Zaitseva NM, Pushkartin GV, Pyatin BM, Morozovk IS, Kislyak NA, Shcherbakova OV, Bykov NP,"Method of synthesis of n-(4-bromophenyl)-n-(2-adamantyl)amine",issued 27 October 1995
  34. RU 860446,Waldman AV, Zaitseva NM, Klimova NV, Lavrova LN, Morozovn IS, Shmar MI, Shcherbakova OV, Yakubov AA, Strekalova SN, Petukhov AG,"Substituted n-adamantilanilines possessing psychostimulating activity",issued 1993, assigned to Cherkasskij Z Khimreaktivov
  35. Averin AD, Ulanovskaya MA, Kovalev VV, Buryak AK, Orlinson BS, Novakov IA, et al. (2010). "Palladium-catalyzed amination of isomeric dihalobenzenes with 1- and 2-aminoadamantanes". Russian Journal of Organic Chemistry. 46 (1): 64–72. doi:10.1134/S1070428010010069. S2CID   85441518.
  36. 1 2 Stiver HG (27 October 2006). "Treatment of Influeza". In Mandell L, Woodhead M, Ewig S, Torres A (eds.). Respiratory Infections. CRC Press. pp. 243–. ISBN   978-0-340-81694-3.
  37. 1 2 Oertel WH, Fahn S (2003). "Parkinsonism". In Brandt T (ed.). Neurological Disorders: Course and Treatment. Gulf Professional Publishing. pp. 1047–. ISBN   978-0-12-125831-3.
  38. Nakamura T, Lipton SA (6 October 2009). "Excitatory Amino Acids, S-Nitrosylation, and Protein Misfolding in Neurodegenerative Diseases: Protection by Memantine and NirotMemantine at NMDA-Gated". In Channels Packer L, Sies H, Eggersdorfer M, Cadenas E (eds.). Micronutrients and Brain Health. CRC Press. pp. 71–. ISBN   978-1-4200-7352-2.
  39. Krapivin SV, Sergeeva SA, Morozov IS (1998). "Comparative analysis of the effects of adapromine, midantane, and bromantane on bioelectrical activity of rat brain". Bulletin of Experimental Biology and Medicine. 125 (2): 151–155. doi:10.1007/BF02496845. ISSN   0007-4888. S2CID   21940190.
  40. Gabbard GO (2007). "Dementia Due to Frontotemporal Lobar Degeneration". Gabbard's Treatments of Psychiatric Disorders. American Psychiatric Pub. pp. 174–. ISBN   978-1-58562-216-0.
  41. Krapivin SV, Sergeeva SA, Morozov IS (November 1993). "[A quantitative pharmaco-electroencephalographic analysis of the action of bromantane]". Biulleten' Eksperimental'noi Biologii I Meditsiny (in Russian). 116 (11): 515–518. doi:10.1007/BF00805158. PMID   8312546. S2CID   34884133.
  42. Burnat P, Payen A, Le Brumant-Payen C, Hugon M, Ceppa F (September 1997). "Bromontan, a new doping agent". Lancet. 350 (9082): 963–964. doi: 10.1016/S0140-6736(05)63310-7 . PMID   9314900. S2CID   34909949.
  43. Siuniakov SA, Grishin SA, Teleshova ES, Neznamov GG, Seredenin SB (2006). "[Pilot clinical trial of ladasten]". Eksperimental'naia i Klinicheskaia Farmakologiia (in Russian). 69 (4): 10–15. PMID   16995430.