Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs.
BACKGROUND
Centrally muscle relaxants (CMRs) are used mainly for treating muscle spasticities of neurological origin, and painful muscle spasms due to rheumatologic conditions. Their use is frequently associated with dose-limiting adverse effects. New drugs with improved side-effect characteristics are badly needed. However, there is no general agreement in the pharmacological literature on what methods are adequate to assess CMR effect and side effects in behaving rodents, which may hinder the development of new drugs. Here we report on the establishment of a simple pharmacological test battery, which was used to compare efficacies and side effect profiles of 11 compounds with central muscle relaxant action, in mice (intraperitoneal application).


METHODS
For measuring muscle relaxant activity, (1) a new tremor model (GYKI 20039-induced tremor) and (2) the morphine-induced Straub-tail assay were used. The former, newly developed method has advantages over harmaline- or LON-954-induced tremor. For detecting side effect liability (ataxia, sedation, impairment of voluntary motor functions), (1) the rota-rod test, (2) measurement of spontaneous motility, (3) the weight-lifting test and (4) the thiopental sleep test were used.


RESULTS
Among the 11 muscle relaxant compounds tested (tolperisone, eperisone, silperisone, diazepam, baclofen, tizanidine, afloqualon, mephenesin, zoxazolamine, memantine and carisoprodol), the calculated safety ratios (i.e. ID50 for side effect/ID50 for muscle relaxant effect) varied in a wide range. Silperisone seems to have the most advantageous profile (safety ratios range between 1.7 and 3.3 in the different pairs of assays) compared to the other tested drugs with lower (one or more ratios below 1.5, and often far below 1) and more varying ratios.


CONCLUSIONS
Therapeutic indices calculated from the results of these in vivo experiments for the clinically used muscle relaxants are in agreement with their adverse effect profiles in humans. Thus the present test battery seems to be suitable for predicting the possible clinical utility of newly synthesized compounds.
Farkas
Sándor
S
Pharmacological Research Centre, Gedeon Richter Ltd. H-1475, Budapest, 10, POB 27, Hungary. s.farkas@richter.hu
Berzsenyi
Pál
P
Kárpáti
Egon
E
Kocsis
Pál
P
Tarnawa
István
I
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001555:Benzene Derivatives / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004357:Drug Synergism; D006246:Harmaline / Q000633:toxicity; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000009:adverse effects / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D020280:Sertraline / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects; D013045:Species Specificity; D013239:Stereotyped Behavior / Q000187:drug effects; D013844:Thiazoles / Q000633:toxicity; D013874:Thiopental / Q000494:pharmacology; D014049:Tolperisone / Q000494:pharmacology; D016896:Treatment Outcome; D014202:Tremor / Q000139:chemically induced / Q000517:prevention & control*; D014508:Urea / Q000031:analogs & derivatives / Q000633:toxicity
D001418:Baclofen; D001555:Benzene Derivatives; D015283:Citalopram; D006246:Harmaline; D007650:Ketanserin; D009020:Morphine; D009125:Muscle Relaxants, Central; D010880:Piperidines; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D013844:Thiazoles; D013874:Thiopental; D014049:Tolperisone; D014508:Urea; C511090:GYKI 20039; C014908:LON 954; C445662:silperisone