PMS-Baclofen Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action (MOA): The precise mechanisms of action of baclofen are not fully known. It inhibits both monosynaptic and polysynaptic reflexes at the spinal level, probably by hyperpolarization of afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Although baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA), there is no conclusive evidence that actions on GABA systems are involved in the production of its clinical effects.
Peak plasma concentrations of baclofen are achieved within 2 hours and the plasma half-life is 2 - 4 hours.
CLINICAL TRIALS: Comparative Bioavailability Study: A bioavailability study was performed to compare the plasma levels produced after a single oral dose administration of two different formulations of baclofen 20 mg to 24 healthy volunteers in order to test their bioequivalency.
The results of the investigation show that the pharmacokinetic profile of the Pharmascience Inc. baclofen formulation is almost superimposable to the one of the reference formulation, thus proving its bioequivalency. (See Table 1.)

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DETAILED PHARMACOLOGY: Baclofen exerted a pronounced muscle-relaxant effect in the non-anesthetized mouse, rabbit, cat, and dog. Doses of up to 10 mg/kg p.o. did not affect coordination in mice. IV doses of 1 or 2 mg/kg decreased polysynaptic (flexor) spinal reflexes in anesthetized rabbits or cats respectively by 50%. A similar reduction was found in decerebrated or spinal cats. The monosynaptic (extensor) spinal reflex was reduced 50% by a dose of 0.5 mg/kg IV in spinalized, decerebrate, or anesthetized cats. Baclofen had no direct effect on the alpha-motor nerve fibres, neuromuscular transmission, or contraction of extrafusal muscle fibres in anesthetized cats. An IV dose of 0.8 mg/kg diminished the tonic activity of gamma motoneurons in decerebrate cats by 50%. Baclofen diminished or abolished decerebrate rigidity in cats in doses of 1-3 mg/kg. It had no effect on the de-efferented muscle spindle or the slowly-adapting pulmonary stretch receptors in anesthetized cats.
Baclofen had anticonvulsive effects against thiosemicarbazide and pentetrazole-induced convulsions in mice but had no effect against electroshock or strychnine-induced convulsions.
An IV dose of 3-6 mg/kg exerted a hypnotic effect in the unanesthetized dog.
Large doses impaired respiration in mice, rabbits, and dogs. Doses of 1 mg/kg IV produced a fall in the blood pressure of anesthetized rabbits or cats, but 3 mg/kg IV had no effect on the blood pressure, heart rate, ECG, or respiration of unanesthetized dogs.
In man, a single oral dose of 10 mg of baclofen is rapidly and almost completely absorbed, whereas absorption of 20 mg and 40 mg doses is less complete. Animal studies indicate rapid distribution throughout the body except to the CNS where concentrations are lower than average. The decay in CNS concentration is, however, slower than the decay from other tissues.
About 85% of a single oral dose is excreted unchanged in the urine. The remaining 15% is mainly deaminated to ß-(p-chlorophenyl)-γ-hydroxybutyric acid within 24 hours. Baclofen is about 30% bound to serum proteins.
Pharmacokinetics: Special Populations: Geriatrics (aged 65 years or above): Following a single oral dose, elderly patients have a slower rate of absorption and elimination, a slightly prolonged elimination half-life, but a similar systemic exposure of baclofen compared to young adults.
Hepatic Impairment: No pharmacokinetic data is available in patients with hepatic impairment after administration of baclofen. However, as the liver does not play a significant role in the disposition of baclofen, it is unlikely that baclofen pharmacokinetics would be altered to a clinically significant level in patients with hepatic impairment.
Renal Impairment: No controlled clinical pharmacokinetic study is available in patients with renal impairment after administration of baclofen. Baclofen is predominantly eliminated unchanged in urine. Sparse plasma concentration data collected in female patients under chronic hemodialysis or compensated renal failure indicate significantly decreased clearance and increased half-life of baclofen in these patients. Severe neurological outcomes have been reported in patients with renal impairment after oral administration, thus pms-BACLOFEN should be given with special care and caution in these patients (see Renal Impairment under WARNINGS).
Toxicology: Acute Toxicity: (See Table 2.)

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The toxic symptoms in mice and rats included ataxia, clonic-tonic convulsions and respiratory paralysis. (See Table 3.)

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Chronic Toxicology: (See Table 4.)

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Teratology and Reproduction Studies: Reproductive Toxicity: Oral baclofen showed no significant adverse effects on fertility or postnatal development at non-maternally toxic dose levels in rats (approximately 2.1-times the maximum oral mg/kg dose in adults). At maternally toxic dose levels (8.3-times the maximum oral mg/kg dose in adults), baclofen increased the incidence of omphaloceles (ventral hernias) in rats, an effect not seen in mice or rabbits. Delayed fetal growth (ossification of bones) in the fetuses of rats and rabbits was also observed at maternotoxic doses.
Rat: Doses of 4.4-5 mg/kg/day and 17.7-21.3 mg/kg/day were administered orally to two groups of female rats during pre-mating, mating, gestation, and lactation. The only significant effect was a reduction in litter size and survivability of offspring (possibly due to agalactia) in the high-dose group. In another rat study, doses of 5 and 10 mg/kg/day were administered by gavage during the last trimester of pregnancy and throughout the lactation period. Five of 31 dams in the high-dose group showed severe weight loss from days 15-21 of gestation as well as agalactia and the entire litter of each of these dams died by day 2 post-partum. In a third study, baclofen doses of 30 mg/kg/day produced symptoms of ataxia and drowsiness in dams and the death of 4 of 24 dams dosed from gestation Days 1 to 12. At this high dose level, there was a slight increase in the resorption rate; however, the number and size of the fetuses remained normal and no malformations were reported.
Rat and Mouse: Doses of 5 mg/kg/day and 20 mg/kg/day were administered by gavage to two groups of pregnant rats on days 6-15 of gestation. The only significant finding was the presence of abdominal hernias in 4/160 fetuses in the high-dose group. In a second similar study, 1/229 control fetuses and 6/293 fetuses from dams receiving 20 mg/kg/day had abdominal hernias. Comparable lesions did not occur in a similar mouse study.
The average number of stillbirths or viable newborns did not differ significantly between control and medicated groups. The average weight of neonates from the high-dose group was significantly reduced.
Rabbit: Doses of 1, 5, and 10 mg/kg/day were administered by gavage to groups of rabbits from the 6th to 18th day of gestation. There was an increased incidence of unossified phalangeal nuclei of forelimbs and hind-limbs in the fetuses from the high-dose group. In another study, a slight increase in resorption rates and the number of rabbits that were non-gravid was observed in rabbits receiving 10 mg/kg/day and 15 mg/kg/day of oral baclofen.
Mutagenicity and Carcinogenicity: Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters.
A 2-year rat study (oral administration of baclofen) found no evidence of carcinogenesis. An apparently dose-related increase in the incidence of ovarian cysts and of enlarged and/or haemorrhagic adrenals at the maximum dose used (50 mg/kg to 100 mg/kg) were observed in female rats treated with baclofen for two years. The clinical relevance of these findings is not known.