Baclofen
- Butyric acid ( RS)- 4-amino- 3-(4 -chlorophenyl)
- (± )-4- amino-3- (4-chlorophenyl ) butyric acid
- Rac -4- amino-3- (4-chlorophenyl ) butyric acid
- DL -4- amino-3- (4-chlorophenyl ) butyric acid
M03BX01
Muscle relaxant
189-191 ° C or 206-208 ° C ( polymorphism )
Risk
145 mg · kg -1 ( LD50, rat, oral)
Template: Infobox chemical / molecular formula search available
Baclofen is a drug from the group of muscle relaxants. It is used for the treatment of spasticity in spinal cord injury and multiple sclerosis. Chemically, it is a chiral derivative of γ -aminobutyric acid, which acts as a specific agonist at the GABAB receptor in mammals. The substance has no effect on the GABA receptor of the fruit fly. Pharmaceutically the racemate of baclofen used.
Physico-chemical properties
Baclofen is a white, odorless, crystalline powder, slightly water-soluble, very slightly soluble in methanol and insoluble in chloroform.
Representation
There are two different ways to synthesize baclofen. By the condensation of two molecules of 4-chlorobenzaldehyde with ethyl acetoacetate, followed by hydrolysis and decarboxylation of a substituted glutaric acid is obtained. Dehydration then leads to cyclic anhydride which is then reacted with ammonia to give the glutarimide. The reaction with an alkaline solution of bromine supplies in a Hofmann rearrangement baclofen.
A second synthetic route starts from 4- Chlorzimtsäureethylester. This is reacted with nitromethane in a nitro - Michael addition in the presence of a base to give β -(4 -chlorophenyl)- γ - nitro- butyric acid ester. The reduction with hydrogen in the presence of Raney nickel gives a β -(4 -chlorophenyl)- γ -aminobutyric acid which leads to ester hydrolysis to baclofen.
Dosage forms
Baclofen can be administered orally or intrathecally ( directly into the cerebrospinal fluid ). The intrathecal administration in spasticity patients is necessary because only a very small amount of the orally administered substance at the site of action depends on the nerves of the spinal cord, and are therefore the only alternative high oral doses with corresponding side effects available.
Intrathecal administration is elected especially in patients with multiple sclerosis who have severe painful spasms and can not be controlled by oral baclofen or other medications. It is a test dose administered to demonstrate the effectiveness. If the test dose was successful, a catheter is placed intrathecally, via a computer-controlled implantable pump supplies the drug as a continuous therapy. The reservoir of the pump can be refilled through the skin from outside again. Disadvantage of the pump system is its price and the complex implantation and care, so that a strict patient selection is necessary.
History
Baclofen was originally developed as a drug for the treatment of epilepsy. The first time it was synthesized by chemist Heinrich Keberle 1962 in the former Ciba -Geigy. The antiepileptic efficacy was disappointing, the antispastic effect but usable. Baclofen was and is still administered orally with varying success. In critically ill children, however, the necessary oral dose is so large that the side effects limit the therapy. How and when baclofen was first used intrathecally, is no longer determine exactly, but it is now an established method of treatment of spasticity.
Great response received baclofen lately by a book by Olivier Ameisen in which he claimed, his alcoholism by baclofen defeated to have. In fact, studies also showed that baclofen has an extraordinary effect in the fight against alcohol addiction: A study reached approximately twice as many patients abstinence from alcohol baclofen as the group of subjects without baclofen.
Effect
Baclofen acts on the synapses and nerves of the spinal cord. Without appropriate permanent control from the brain outweigh the spastic reflex mechanisms in the spinal cord. These can be so strong that they wake up from sleep and feel pain in patients.
Baclofen acts on the reflex arcs of the spinal cord. Especially at the so-called Renshaw cells may mimic the natural antispasmodic effect of GABA. The necessary dose of intrathecal Baclofens is different, but is far smaller than the oral dose.
Pharmacokinetics
The substance is readily absorbed after oral administration and is distributed throughout the body. Biotransformation hardly takes place. The drug is excreted largely unchanged by the kidney.
Overdose
The following symptoms of baclofen overdose can occur:
- Nausea
- Vomit
- Dizziness
- Respiratory failure
- Altered pupillary
- Decreased blood pressure (hypotension)
- Decreased heart rate ( bradycardia)
- Decreased body temperature ( hypothermia)
- Coma
Other areas of application
For more than 10 years, the effect of baclofen as GABA-B receptor agonist in the treatment of addiction, anxiety, and depression is explored.
For the treatment of alcoholism with baclofen a number of scientific studies with positive results were published.
On March 14, 2014, the French authorities for drug safety ANSM spoke a limited three-year recommendation to use (RTU ) of baclofen for the treatment of alcoholism with which unit in France removes the legal uncertainty in the prescription of baclofen and the effectiveness is confirmed. Two double-blind, placebo-controlled studies with prospective evaluation of the end of 2014/2015 were approved in the year 2012 by the ANSM and are currently in progress ( BACLOVILLE and ALPADIR ). The effectiveness was confirmed by field studies. In Germany there are currently (as of April 2014) no approval for the treatment of alcohol dependence; a prescription is possible in individual cases off-label.
Baclofen as an imported drug may reduce obviously the reflux episodes, belching and pH - metric phases of pH < 4.0 in GERD according to a double-blind study.
The importance of the GABA-B receptors for the development of anxiety was studied and demonstrated in various studies, in this context the suitability of baclofen for the treatment of anxiety and depression in animal experiments. A 2010 clinical study, James Garbutt et al. USA, on the other hand found no significant results over placebo.
Commercial preparations
Lebic (D), Lioresal (D, A, CH ) and generic (D, CH)