Pharmacotherapeutics in fibrositis.

Fibrositis (fibromyalgia) is best treated by attaining patient acceptance of and compliance with a comprehensive treatment program. This includes education, physical therapy, muscle and mental relaxation, examination and adjustment of goals and priorities, and pacing of activities, as well as pharmacotherapeutics. Of the medications in use, anti-inflammatory agents with a high degree of analgesia are more effective than "pure" anti-inflammatory agents. Tricyclic derivatives are beneficial muscle relaxants. The use of long-acting agents improves compliance and is therefore favored. Local agents are of adjunctive value in some cases. Double-blind, placebo-controlled studies show Cyclobenzaprine ( Flexeril ) to be an effective medication in the treatment of fibrositis (fibromyalgia).

Amitriptyline sensitization of a serotonin-mediated behavior depends on the passage of time and not repeated treatment.

Daily treatment for 10 days with either amitriptyline or the tricyclic muscle relaxant, Cyclobenzaprine ( Flexeril ), increased the incidence of head-twitch behavior in response to 5-hydroxytryptophan (5-HTP) when this was examined two days later. Only one day of amitriptyline treatment followed by an 11-day hiatus before administration of 5-HTP also sensitized the head-twitch response whereas similar amitriptyline treatment followed by 5-HTP one hour later failed to do so. These data provide the first evidence for time-dependent sensitization of brain serotonin systems.

Oral osmotic delivery systems containing polyethylene oxide (PEO, a water-swellable polymer) were designed and the release of Cyclobenzaprine ( Flexeril ) hydrochloride (model drug) from the devices was investigated. The systems consisted of model drug, mannitol (osmotic agent), and increasing amounts of PEO surrounded by a semipermeable membrane drilled with a delivery orifice. There was a decrease in drug release rate with PEO in the core. This may be due to solubility-modulating properties of the polymer. Visual inspection of the devices with PEO showed significant swelling during dissolution testing. Swelling (internal pressure) may influence water inhibition rate into the core and subsequently drug release rate. The release rates were a function of membrane thickness. The release rates were independent of orifice size (range of 150-510 microns diameter) and hydrodynamic conditions for the devices. This would be advantageous in the delivery of drugs in man.

Human liver aldehyde oxidase: inhibition by 239 drugs.

The authors tested 239 frequently used drugs and other compounds for their potential to inhibit the drug-metabolizing enzyme, aldehyde oxidase, in human liver cytosol. A sensitive, moderate throughput HPLC-MS assay was developed for 1-phthalazinone, the aldehyde oxidase-catalyzed product of phthalazine oxidation. Inhibition of this activity was examined for the 239 drugs and other compounds of interest at a test concentration of 50 microM. Thirty-six compounds exhibited greater than 80% inhibition and were further examined for measurement of IC50. The most potent inhibitor observed was the selective estrogen receptor modulator, raloxifene (IC50=2.9 nM), and tamoxifen, estradiol, and ethinyl estradiol were also potent inhibitors. Other classes of drugs that demonstrated inhibition of aldehyde oxidase included phenothiazines, tricyclic antidepressants, tricyclic atypical antipsychotic agents, and dihydropyridine calcium channel blockers, along with some other drugs, including loratadine, Cyclobenzaprine ( Flexeril ), amodiaquine, maprotiline, ondansetron, propafenone, domperidone, quinacrine, ketoconazole, verapamil, tacrine, and salmeterol. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which aldehyde oxidase is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme.