Cyclobenzaprine ( Flexeril ) and ethanol interaction.

The effects of Cyclobenzaprine ( Flexeril ), a tricyclic compound, on the central depressant action of ethanol and on hepatic ethanol metabolizing enzymes were studied in rodents. Administration of Cyclobenzaprine ( Flexeril ), 5 mg/kg, IP, 30 min prior to a narcotic dose of ethanol solution, 5 g/kg, IP, enhanced ethanol-produced narcosis in mice. This effect was greater in male than in female mice. Cyclobenzaprine ( Flexeril ) inhibited endogenous rat liver alcohol dehydrogenase in vitro in the concentration range between 10(-5) M and 10(-6)M. Cyclobenzaprine ( Flexeril ) exerted little effect on hepatic aldehyde dehydrogenase in vitro. The results suggest that Cyclobenzaprine ( Flexeril ) possesses depressant properties and inhibition of liver alcohol dehydrogenase may underlie the observed behavioral response studied. It is concluded that alteration of endogenous liver alcohol dehydrogenase by certain tricyclic antidepressant drugs may be involved in the mechanism(s) of their toxic interaction with ethanol.

Pharmacological approaches other than opioids in chronic non-cancer pain management.

Many pains are controlled by non-addictive procedures ranging from exercise to a variety of analgesic medications. Some pains are controlled by analgesic drugs, but at the cost of intolerable side effects. This is true both for non-steroidal anti-inflammatory drugs and opioids. The worst pains are most often controlled by opioids, but problems of tolerance and addiction limit these successes. This contribution provides a statement on non-addictive, non-opioid drugs which help to control pain. Just as these vary in their success, so they vary also in the strength of the scientific evidence which supports their use. The groups of drugs to be considered can be evaluated in three respects; evidence of analgesic effect in controlled trials; evidence of side-effects compared with control substances and with standard experience; evidence of usefulness in clinical practice. The latter which is the most important for practice often has the least scientific proof. Six main classes of drugs are recognized which provide analgesic effects, other than opioids. 1) Non-steroidal anti-inflammatory drugs are widely accepted as analgesics on the basis of animal studies, numerous controlled investigations and clinical practice. Acetaminophene may not be anti-inflammatory, but is recognized as an effective analgesic which in many other respects resembles the above. 2) Muscle relaxants, e.g. Cyclobenzaprine ( Flexeril ) or baclofen have varied actions, but often provide some relief of pain. 3) Antidepressants may be analgesic if they relieve depression which is giving rise to pain. This applies to all anti-depressants. Some antidepressants have been shown to be analgesic in the absence of depression. The best accredited of these is amitriptyline. Antidepressants too have significant side effects. A serotoninergic hypothesis is insufficient to explain the actions of antidepressants in relieving pain in the absence of depression. 4) Phenothiazine neuroleptics (and possibly some others) may be analgesic. Drugs reported to be analgesic include chlorpromazine, fluphenazine, perphenazine, trifluoperazine, methotrimeprazine (levomepromazine) among others. Haloperidol has also been utilized. Well controlled evidence exists with the use of methotrimeprazine (levomepromazine) used as an injection. The analgesic effect of oral neuroleptics is less well established and mostly depends upon clinical observation, withdrawal and re-challenge. 5) Anticonvulsants. 6) Other drugs. Non-steroidal anti-inflammatory drugs and some muscle relaxants, e.g. Cyclobenzaprine ( Flexeril ) are best used in the short term. The gastrointestinal side effects of non-steroidal anti-inflammatory drugs have been quite troublesome and over 2% of patients followed over five years are at risk of developing peptic ulceration from such medication. Cyclobenzaprine ( Flexeril ) is best used in short term treatment, but may be used intermittently for chronic pain. Antidepressants, neuroleptics, anticonvulsants and some other drugs can be used long term. Topical analgesic agents may also be used.

Identification of human liver cytochrome P450 isoforms involved in the in vitro metabolism of Cyclobenzaprine ( Flexeril ).

Cyclobenzaprine ( Flexeril ) is a muscle relaxant, possessing a tricyclic structure. Numerous therapeutic agents containing this structure are known to be metabolized by polymorphic cytochrome P4502D6. The aim of this study was to determine if cytochrome P4502D6 and other isoforms are involved in the metabolism of Cyclobenzaprine ( Flexeril ) in human liver microsomes. Selective cytochrome P450 inhibitors for CYP1A1/2 (furafylline and 7,8-benzoflavone) and CYP3A4 (troleandomycin, gestodene, and ketoconazole) inhibited the formation of desmethylCyclobenzaprine ( Flexeril ), a major metabolite of Cyclobenzaprine ( Flexeril ), in human liver microsomes. Antibodies directed against CYP1A1/2 and CYP3A4 inhibited the demethylation reaction whereas anti-human CYP2C9/10, CYP2C19, and CYP2E1 antibodies did not show any inhibitory effects. When a panel of microsomes prepared from human B-lymphoblastoid cells that expressed specific human cytochrome P450 isoforms were used, only microsomes containing cytochromes P4501A2, 2D6, and 3A4 catalyzed N-demethylation. In addition, demethylation catalyzed by these recombinant cytochromes P450 can be completely inhibited with selective inhibitors at concentrations as low as 1 to 20 microM. Interestingly, Cyclobenzaprine ( Flexeril ) N-demethylation was significantly correlated with caffeine 3-demethylation (1A2) and testosterone 6 beta-hydroxylation (3A4) but not with dextromethorphan O-demethylation (2D6) in human liver microsomes. To further determine the involvement of cytochrome P4502D6 in Cyclobenzaprine ( Flexeril ) metabolism, liver microsomes from a human that lacked CYP2D6 enzyme activities was included in this study. The data showed that Cyclobenzaprine ( Flexeril ) N-demethylation still occurred in the incubation with this microsome. These results suggested that cytochrome P4502D6 plays only a minor role in Cyclobenzaprine ( Flexeril ) N-demethylation whereas 3A4 and 1A2 are primarily responsible for Cyclobenzaprine ( Flexeril ) metabolism in human liver microsomes. Due to the minimum involvement of CYP2D6 in the vitro metabolism of Cyclobenzaprine ( Flexeril ), the polymorphism of cytochrome P4502D6 in man should not be of muci concern in the clinical use of Cyclobenzaprine ( Flexeril ).

Ocular aldehyde dehydrogenase in rodents.

The presence of NAD-dependent ocular aldehyde dehydrogenase in rodents is reported. The enzyme is species and strain-dependent. Ocular ALDH possesses a significantly greater specific activity than that of the hepatic tissue of the species studied. d-Amphetamine non-competitively inhibited rat eye ALDH in vitro. Short-term administration of Cyclobenzaprine ( Flexeril ), a tricyclic compound with muscle relaxant property, induced ocular aldehyde dehydrogenase. This is compared with lack of effect of certain CNS-stimulants, ethanol intake and of a monoamine oxidase inhibitor on endogenous ALDH in vivo.