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Bromantane, sold under the brand name Ladasten, is an atypical central nervous system (CNS) psychostimulant 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 Serotonin neurotransmitter systems, its exact mechanism of action is unknown, and is distinct in its properties relative to typical stimulants such as amphetamine. Bromantane has sometimes been described as an actoprotector (synthetic adaptogen).
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. 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. The therapeutic benefit against asthenia was observed to still be present one month after discontinuation of the drug. 3% of patients experienced side effects; though none were considered serious; and 0.8% of patients discontinued treatment due to side effects. Bromantane was also noted to normalize the sleep-wake cycle.
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. It has also been found to increase sexual receptivity and proceptivity in rats of both sexes, which was attributed to its dopaminergic actions. It has been proposed that bromantane may suppress prolactin levels by virtue of its dopaminergic properties as well. Bromantane has been found to "agonize" amphetamine-induced stereotypies in vivo, suggesting that it might potentiate certain effects of other stimulants.
The stimulant effects of bromantane onset gradually within 1.5–2 hours and last for 8–12 hours when taken orally.
A selection of quoted excerpts from the medical literature detail the differences between bromantane and typical stimulants:
Bromantane is well tolerated and elicits few (including peripheral sympathomimetic effects and hyperstimulation), does not appear to produce drug tolerance or drug dependence, has not been associated with drug withdrawal symptoms upon discontinuation, and displays an absence of addiction potential, contrary to typical stimulants. In accordance with human findings, animals exposed to bromantane for extended periods of time do not appear to develop tolerance or dependence.
The precise direct molecular mechanism of action by which bromantane ultimately acts as a dopamine synthesis enhancer is unknown. However, it has been determined that activation of certain cAMP-, calcium, and phospholipid-dependent such as protein kinase A and especially protein kinase C corresponds with the manifestation of the pharmacological effects of bromantane. Bromantane may activate intracellular signaling cascades by some mechanism (e.g., agonist some as-yet-undetermined receptor) to in turn activate protein kinases, which in turn cause increased transcription of TH and AAAD.
The related drugs amantadine and memantine also have many properties similar to those of bromantane.
Researchers discovered that amantadine and memantine bind to and act as 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.
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.
The rate of absorption in women is greater than in men, with maximum blood concentrations being reached at 2.75 and 4 hours after oral administration, respectively.
The main metabolite of bromantane is 6β-hydroxybromantane.
Closely related with similar effects include adapromine, amantadine, chlodantane, gludantane (gludantan), memantine, and rimantadine.
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.)". It was found to produce more marked and prolonged stimulant effects than the other adamantanes, and eventually entered use. The drug was notably given to soldiers in the Soviet and Russian militaries to "shorten recovery times after strong physical exertion". 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). 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.
Bromantane was eventually repurposed in 2005 as a treatment for neurasthenia. It demonstrated effectiveness and safety for the treatment of the condition in extensive, large-scale , and was approved for this indication in Russia under the brand name Ladasten sometime around 2009.
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