J Toxicol Clin Toxicol. 1997;35(1):77-82.
Evaluation of a colloidal metal immunoassay device for the detection of tricyclic antidepressants in urine.

Poklis A, Edinboro LE, Lee JS, Crooks CR.

Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0165, USA.

BACKGROUND: The sensitivity and selectivity of a colloidal metal immunoassay device (Triage Plus TCA) which is designed for the rapid detection of tricyclic antidepressant drugs in urine at a total tricyclic antidepressant concentration of 1000 ng/mL or greater were evaluated. METHODS: The sensitivity of the Triage Plus assay was determined by adding known amounts of amitriptyline, nortriptyline, imipramine, desipramine, doxepin and desmethyl-doxepin to drug free urine. The selectivity of the assay was determined by adding known concentrations of 32 drugs or drug metabolites commonly encountered in emergency department admissions to drug free urine. Triage Plus results from clinical urine specimens containing either amitriptyline, nortriptyline, imipramine, desipramine, doxepin and desmethyl-doxepin were compared to those obtained with thin layer chromatography and high performance liquid chromatography. RESULTS: Triage Plus yielded a positive response to gravimetrically prepared urines of tricyclic antidepressant at the stated cut-off value (1,000 ng/mL), and at 80% (800 ng/mL) and 50% (500 ng/mL) of the cut-off with amitriptyline, nortriptyline, imipramine, desipramine and doxepin. Other tricyclic antidepressant drugs, clomipramine and protriptyline were positive at 1000 ng/mL. Significant cross-reactivity was observed only with cyclobenzaprine at 1000 ng/mL. No significant cross reactivity was found at 1.0 g/L for 32 drugs commonly encountered in emergency department admissions. A 95% (70/74) agreement of positive tricyclic antidepressant results was observed between Triage Plus and thin layer chromatography. Discordant urines were found by high performance liquid chromatography to contain tricyclic antidepressant concentrations below the cut-off value of the colloidal metal assay. CONCLUSION: Triage Plus was found to be an accurate device for the detection of tricyclic antidepressants in urine at the stated cut-off value of 1000 ng/mL tricyclic antidepressant. With the exception of cyclobenzaprine, significant cross-reactivity was not observed with other drugs commonly encountered in emergency department admissions.

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FEMS Microbiol Lett. 1996 May 1;138(2-3):221-6.
Phase I and phase II enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics.

Zhang D, Yang Y, Leakey JE, Cerniglia CE.

National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.

The filamentous fungus Cunninghamella elegans has the ability to metabolize xenobiotics, including polycyclic aromatic hydrocarbons and pharmaceutical drugs, by both phase I and II biotransformations. Cytosolic and microsomal fractions were assayed for activities of cytochrome P450 monooxygenase, aryl sulfotransferase, glutathione S-transferase, UDP-glucurono-syltransferase, UDP-glucosyltransferase, and N-acetyltransferase. The cytosolic preparations contained activities of an aryl sulfotransferase (15.0 nmol min-1 mg-1), UDP-glucosyltransferase (0.27 nmol min-1 mg-1) and glutathione S-transferase (20.8 nmol min-1 mg-1). In contrast, the microsomal preparations contained cytochrome P450 monooxygenase activities for aromatic hydroxylation (0.15 nmol min-1 mg-1) and N-demethylation (0.17 nmol min-1 mg-1) of cyclobenzaprine. UDP-glucuronosyltransferase activity was detected in both the cytosol (0.09 nmol min-1 mg-1) and the microsomes (0.13 nmol min-1 mg-1). N-Acetyltransferase was not detected. The results from these experiments provide enzymatic mechanism data to support earlier studies and further indicate that C. elegans has a broad physiological versatility in the metabolism of xenobiotics.

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Acta Anaesthesiol Scand. 1997 Jan;41(1 Pt 2):187-90.
Pharmacological approaches other than opioids in chronic non-cancer pain management.

Merskey H.

London Psychiatric Hospital, Ontario, Canada.

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 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 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.

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J Clin Pharmacol. 1977 Nov-Dec;17(11-12):719-27.
Plasma levels and bioavailability of cyclobenzaprine in human subjects.

Hucker HB, Stauffer SC, Albert KS, Lei BW.

Cyclobenzaprine [Flexeril] was extensively metabolized in man, less than 1% of the dose being excreted unchanged in the urine. Comparison of areas under plasma level curves (AUC) after oral and intravenous doses suggests that the drug may be partly metabolized in the lumen or during its first passage through the gut wall and/or liver. Average plasma levels of the drug increased with increasing dosage, but the AUC increased less rapidly with increasing dose, possibly because of dose-dependent absorption.

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