General Description
Odorless or practically odorless white to off-white crystalline powder.
Reactivity Profile
BACLOFEN(1134-47-0) is an amine. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.
Air & Water Reactions
Insoluble in water.
Health Hazard
SYMPTOMS: Symptoms of exposure to this compound via ingestion may include drowsiness, insomnia, dizziness, weakness, mental confusion, nausea, constipation, anorexia, urinary retention, impotence, nystagmus, diplopia and incoordination. Ingestion may lead to cholinergic effects and lassitude. It may also lead to ataxia. Other symptoms due to ingestion may include impaired renal function, fatigue, headache, hypotension, urinary frequency, rash, pruritis, ankle edema, excessive perspiration, weight gain, nasal congestion, and rarely, euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, tremor, rigidity, dystonia, blurred vision, strabismus, miosis, mydriasis, dysarthia, epileptic seizure, dyspnea, palpitation, chest pain, syncope, dryness of the mouth, taste disorder, abdominal pain, vomiting, diarrhea, blood in the stools, enuresis, dysuria, inability to ejaculate, nocturia and hematuria. Overexposure through ingestion may result in seizures, and coma with respiratory depression. Aspiration pneumonia is a frequent complication of coma with respiratory depression. Other symptoms due to overdosage may include vomiting, muscular hypotonia, drowsiness, and accommodation disorders. Cyanosis has been reported. Chronic ingestion may result in drowsiness, depression, weakness, anxiety, ataxia, headaches, blurred vision, gastric upset and pruritic skin rashes characterized by urticaria or erythematous macular eruptions. Sudden withdrawal after chronic ingestion may cause auditory and visual hallucinations, anxiety and tachycardia. Seizures may also occur after sudden withdrawal. Abuse may lead to drug dependence.
Fire Hazard
Flash point data for this chemical are not available. BACLOFEN is probably combustible.
Originator
Lioresal,Ciba Geigy,Switz.,1971
Definition
ChEBI: A monocarboxylic acid that is butanoic acid substituted by an amino group at position 4 and a 4-chlorophenyl group at position 3. It acts as a central nervous system depressant, GABA agonist and muscle relaxant.
Manufacturing Process
42.45 g of β-(p-chlorophenyl)glutaric acid imide are stirred into a solution of
8.32 g of sodium hydroxide in 200 ml of water. The mixture is heated for 10
minutes at 50°C, and the solution thus formed is cooled to 10° to 15°C. At
this temperature there are then added dropwise a solution of 40.9 g of
sodium hydroxide in 200 ml of water and then, in the course of 20 minutes,
38.8 g of bromine. When all has been dropped in, the batch is stirred for 8
hours at 20° to 25°C. The reaction solution is then cautiously adjusted with
concentrated hydrochloric acid to pH 7, whereupon finely crystalline γ-amino-
β-(p-chlorophenyl)butyric acid settles out. To purify it, it is recrystallized from
water. Melting point is 206°to 208°C.
Brand name
Kemstro
(Schwarz Pharma); Lioresal (Medtronic); Lioresal (Novartis).
Therapeutic Function
Muscle relaxant
Biological Functions
Baclofen (Lioresal) is the parachlorophenol analogue
of the naturally occurring neurotransmitter γ-aminobutyric
acid (GABA).
Biological Activity
Selective GABA B receptor agonist. Skeletal muscle relaxant.
Biochem/physiol Actions
Baclofen, a γ-aminobutyric acid (GABA) analog, possesses myorelaxant properties Being a γ-aminobutyric acid receptor B (GABAB) agonist, baclofen may be involved in the potentiation of dendritic potassium K+?channels. It may be useful in blocking transient lower esophageal sphincter relaxation (TLESR)?in gastroesophageal reflux disease (GERD). Baclofen may also have scope for treating addictive especially, in alcohol use disorder (AUD).
Mechanism of action
Baclofen appears to affect the neuromuscular axis by
acting directly on sensory afferents, γ-motor neurons,
and collateral neurons in the spinal cord to inhibit both
monosynaptic and polysynaptic reflexes. The principal
effect is to reduce the release of excitatory neurotransmitters
by activation of presynaptic GABAB receptors.
This seems to involve a G protein and second-messenger
link that either increases K+ conductance or decreases
Ca++ conductance.
Clinical Use
Baclofen is an agent of choice for treating spinal spasticity
and spasticity associated with multiple sclerosis. It is
not useful for treating spasticity of supraspinal origin.
Doses should be increased gradually to a maximum of
100 to 150 mg per day, divided into four doses.
Safety Profile
Poison by ingestion,subcutaneous and intravenous routes. Human systemiceffects by ingestion: blood pressure lowering, coma,muscle weakness, pulse rate decrease, respiratorydepression. When heated to decomposition it emits toxicfumes of Cl-
Synthesis
Baclofen, 4-amino-3-(4-chlorophenyl)butyric acid (15.3.5), is synthesized in
two ways. According to the first, 4-chlorobenzaldehyde is condensed with two moles of
acetoacetic ester, giving the product (15.3.1), which initially undergoes alkaline hydrolysis
and decarboxylation forming 3-(4-chlorphenyl)glutaric acid (15.3.2). Dehydration of
this gives 3-(4-chlorophenyl)glutaric acid anhydride (15.3.3), and further treatment with
ammonia gives the corresponding glutarimide (15.3.4). Reacting this with an alkaline solution
of a halogen (Hofmann rearrangement) gives baclofen (15.3.6).
Veterinary Drugs and Treatments
Baclofen may be useful to decrease urethral resistance in dogs to
treat urinary retention. It is not recommended for cats.
in vitro
(±)-baclofen dampened cell growth in human hepatocellular carcinoma (hcc) cells in a dose-dependent manner. (±)-baclofen also caused cell cycle arrest at g0/g1 phase without inducing cell death. additionally, (±)-baclofen-evoked hcc cells proliferation was associated with down-regulation of the intracellular camp level, up-regulation of p21waf1 protein expression and its phosphorylation level, which could be reversed by pretreatment with the gabab antagonist, phaclofen, indicating that (±)-baclofen-evoked growth blockade was exerted in a gabab-dependent fashion [1].
in vivo
the mice, subcutaneously injected with bel-7402 cells, were given an intraperitoneal injection of (±)-baclofen 30 mg/kg every day for 30 days. compared with the control, (±)-baclofen remarkably blocked the bel-7402 xenograft tumor growth without causing toxic effects via measuring the relative tumor volume and the mean body weight change in (±)-baclofen-treated groups, which could make (±)-baclofen as an effective and relatively safe potential drug for the treatment of hcc [1].
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: enhanced muscle relaxant effect
with procainamide.
Antidepressants: enhanced muscle relaxant effect
with tricyclics.
Antihypertensives: enhanced hypotensive effect.
Lithium: use with caution.
IC 50
200 nm: a selective agonist of γ-aminobutyric acid metabotropic receptor (b) (gabab).
Metabolism
Baclofen is rapidly and effectively absorbed after oral
administration. It is lipophilic and able to penetrate the
blood-brain barrier.Approximately 35% of the drug is
excreted unchanged in the urine and feces.
References
[1]. wang, t., huang, w., & chen, f. baclofen, a gabab receptor agonist, inhibits human hepatocellular carcinoma cell growth in vitro and in vivo. life sciences. 2008; 82(9-10): 536-541.
