Baclofen

Drug Baclofen (Lioresal] Oral Dosage Adult 5 mg TID initially increase by 5 mg at 3-day intervals as required maximum recommended dosage is 80 mg/day. Children No specific pediatric dosage is listed the adult dose must be decreased according to the size and age of the child. Comments More effective in treating spasticity resulting from spinal cord lesions (versus cerebral lesions]. 

Dantrolene sodium (Dantrium] Adult 25 mg/d initially increase up to 100 mg 2, 3, or 4 times per day as needed maximum recommended dose is 400 mg/day. Children (older than 5 yr of age] initially, 0.5 mg/kg body weight BID increase total daily dosage by 0.5 mg/kg every 4-7 days as needed, and give total daily amount in 4 divided dosages maximum recommended dose is 400 mg/d. Exerts an effect directly on the muscle cell may cause generalized weakness in all skeletal musculature. 

Diazepam (Valium] Adult 2-10 mg TID or QID. Children (older than 6 mo of age] 1.0-2.5 mg TID or QID (in both adults and children, begin at lower end of dosage range and increase gradually as tolerated and needed]. Produces sedation at dosages that decrease spasticity. 

Gabapentin [Neurontin] Adult initially, 300 mg TID. Can be gradually increased up to 3600 mg/d based on desired response. Children (3-12 years of age] Initially, 10-15 mg/kg body weight in 3 divided dosages increase over 3 days until desired effect or a maximum of 50 mg/kg/d. Developed originally as an anticonvulsant may also be helpful as an adjunct to other drugs in treating spasticity associated with spinal cord injury and multiple sclerosis. 

Tizanidine [Zanaflex] Adult 8 mg every 6-8 hours as needed. Children The safety and effficacy of this drug in treating spasticity in children have not been established. May reduce a in spinal cord disorders while producing fewer side effects and less generalized muscle weakness than other agents (oral baclofen, diazepam]. 

Freaney, T.E. and Allen, L.P. U.S. Patent 2,828,246 March 25, 1958 assigned to Commercial Solvents Corporation 

Miescher, G.M. U.S. Patent 3,795,663 March 5,1974 assigned to Commercial SolventsCorp. 

Chemical Name 7-Amino-/3-(p hlorophenyl)butyric acid 

Trade Name Manufacturer Country Year Introdi 

Miescher. G.M. U.S. Patent 3,795,663 March 5,1974 assigned to Commercial Solvents Corp. Kindraka, J.A. and Gallagher, J.B. U.S. Patent 4,101,539 July 18,1978 assigned to IMC Chemical Group, Inc. 

Trade Name Manufecturer Country Year Introdi 

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The y-lactone problem is made easier because the FGs are all based on oxygen. The molecule can therefore be disconnected without FGl except for oxidation or reduction. Let s now look at the synthesis of a molecule with a difficult FG the muscle relaxant baclofen TM 349. What is the difficult FG ... 

Linfolysin - Chlorambucil Linosal - Betamethasone Linostil -Dimetacrine tartrate Linton Haloperidol Linyl - Phentermine HCI Lioresal Baclofen Lipanor - Ciprofibrate Lipenthyl - Fenofibrate Lipentyl - Fenofibrate Lipavil - Clofibrate Lipavlon - Clofibrate Lipenan - Clofibride Lipidax - Fenofibrate Lipidicon - Clofibrate Lipidil - Fenofibrate Lipo - Folic acid Lipo-BC - Inositol... 

GABA is the predominant inhibitory neurotransmitter in the CNS. Baclofen acts centrally as an agonist at the GABAb receptor, which increases inhibition of nerves. 3-Aminopropylphosphinic acid (3-APPi) has been shown experimentally to act as an antitussive at peripheral nerves and preclinical evidence suggests that baclofen indeed has antitussive actions clinically [3]. 

Currently, baclofen is the only clinically used GAB Ab receptor agonist. It is used as a muscle relaxant for treatment of spasticity in spinal injury and multiple sclerosis. The cloning of GABAb receptors has renewed the interest in the search for more selective diugs and novel therapeutic indications. 

The mode of action of many skeletal muscle relaxants, for example carisoprodol (Soma), baclofen (Lioresal), and chlorzoxazone (Paraflex), is not clearly understood. Many of tiiese dragp do not directly relax skeletal muscles, but dieir ability to relieve acute painful musculoskeletal conditions may be due to their sedative action. Cyclobenzaprine (Flexeril) appears to have an effect on muscle tone, tiius reducing muscle spasm. 

The skeletal muscle relaxants are contraindicated in patients with known hypersensitivity. Baclofen is contraindicated in skeletal muscle spasms caused by rheumatic disorders. Carisoprodol is contraindicated in patients with a known hypersensitivity to meprobamate. Cyclobenzaprine is contraindicated in patients with a recent myocardial infarction, cardiac conduction disorders, and hyperthyroidism, hi addition, cyclobenzaprine is contraindicated within 14 days of the administration of a monoamine oxidase inhibitor. Oral dantrolene is contraindicated in patients with active hepatic disease and muscle spasm caused by rheumatic disorders and during lactation. See Chapter 30 for information on diazepam. 

The most useful of the insertion processes is the intramolecular reactions that occur with high selectivity for the formation of five-membered ring products. The electrophilic nature of the process is suggested by C-H bond reactivity in competitive experiments (3°>20 >1°) [76, 77]. Asymmetric catalysis with Rh2(MPPIM)4 has been used to prepare a wide variety of lignans that include (-)-enterolactone (3) [8], as well as (R)-(-)-baclofen (2) [7],2-deoxyxylolactone (31) [80,81],and (S)-(+)-imperanane (32) [82].Enantioselectivities are 91-96%... 

QHiqO 141-97-9) see Aminophenazone Baclofen Cefotaxime Ceftazidime Chloroquine Cloricromen Cloxacillin Dipyridamole Felodipine Flutoprazepam Hymecromone Kawain Lacidipine Leflunomide Methylthiouracil Nevirapine Nitrendipine Oxacillin Pentoxifylline Propyphenazone Sulfamerazine acetoacetic acid 4-(trifluoromethyl)anilide (C H (,F3N02 351-87-1) see Leflunomide acetoacetyl chloride... 

C7H5CIO 104-88-1) see Baclofen Carbinoxamine Chlormezanone Chloropyrainine Nicoclonatc 2-chlorobenzaIdehydc oxime (C7HSCINO 3717-28-0) see Cloxacillin chlorobenzene... 

C12H14CINO4 28311-20-8) see Baclofen 2-chloro-3-nitro-4-methylpyridine (C(jH5C1N202 23056-39-5) see Nevirapine... 

C, H,CIOf, S4S03-73-6) see Baclofen 2, 3 -di-0-acetyl-S -deoxy-5-fluorocytidine... 

CH3NO2 75-52-5) see Baclofen Gabapentin Midazolam Pirbuterol Ranitidine Ropinirole Trometaniol l-(2-nitro-4-methoxyphenyl)-2-nitropropcnc C oHi()N203 25803-11-6) see Clometacin 4-(5-nitro-l-methylindol-3-ylmethyl)-3-methoxybenzoic acid... 

Baclofen ismostpromisingagentat present, but studies with negative findings exist. 

Kranzler HR, Bauer LO, Hersh D, et al Carbamazepine treatment of cocaine dependence a placebo-controlled trial. Drug Alcohol Depend 38 203-211, 1995 Levin FR, Lehman AF Meta-analysis of desipramine an adjunct in the treatment of cocaine addiction. J Clin Pharmacol 11 374-378, 1991 Lima MS, Reisser AA, Soares BG, et al Antidepressants for cocaine dependence. Cochrane Database Syst Rev 4 CD002950, 2001 Ling W, Shoptaw S, Majewska D Baclofen as a cocaine anti-craving medication a preliminary clinical study 0etter). Neuropsychopharmacology 18 403 04, 1998... 

The enantiomerically pure 3-arylglutaric ester are precursors for the synthesis of (—)-paroxetine [10], a selective serotonin reuptake inhibitor used in the treatment of depression, obsessive compulsive disorder, and panic, and (i )-Baclofen [11], a GABAb receptor agonist, which is used cHnically in the treatment of spasticity (Chart 5.1). 

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