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PubMed2005

Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) "probes" for human udp-glucuronosyltransferases.

Relatively few selective substrate and inhibitor probes have been identified for human UDP-glucuronosyltransferases (UGTs). This work investigated the selectivity of trifluoperazine (TFP), as a substrate, and amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone, as inhibitors, for human UGTs. Selectivity was assessed using UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15 expressed in HEK293 cells. TFP was confirmed as a highly selective substrate for UGT1A4. However, TFP bound extensively to both HEK293 lysate and human liver microsomes in a concentration-dependent manner (fuinc 0.20-0.59). When corrected for nonspecific binding, Km values for TFP glucuronidation were similar for both UGT1A4 (4.1 microM) and human liver microsomes (6.1+/-1.2 microM) as the enzyme sources. Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC50 1.5 microM). Using phenylbutazone and quinine as "models," inhibition kinetics were variously described by competitive and noncompetitive mechanisms. Inhibition of UGT2B7 by quinidine was also investigated further, because the effects of this compound on morphine pharmacokinetics (a known UGT2B7 substrate) have been ascribed to inhibition of P-glycoprotein. Quinidine inhibited human liver microsomal and recombinant UGT2B7, with respective Ki values of 335+/-128 microM and 186 microM. In conclusion, TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies. Amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone are nonselective UGT inhibitors.

Cell Line↗

PubMed1995

Idiopathic Subjective Tinnitus Treated by Amitriptyline Hydrochloride/Biofeedback.

The efficiency of two treatment modalities for subjective/idiopathic tinnitus (SIT): biofeedback (BF) and amitriptyline hydrochloride (AT) was investigated in 225 randomly selected subjects. Findings show that after 10 weeks of treatment in the BF group, 43.5% of the patients reported an improvement of tinnitus during activity. In the AT group, 27.5% of patients reported subjective improvement of tinnitus at rest although only 15.8% of the AT patients reported improvement during activity. Biofeedback during rest had a significantly better effect on tinnitus disturbance than AT. No objective diminishment of tinnitus loudness was found as a result of any of the treatment modalities. We believe that BF can help tinnitus patients especially during periods of rest and we also suggest trying tricyclic antidepressant drugs such as AT for treatment of tinnitus patients, in small doses, however, to minimize the side effects of this drug. Subjective tinnitus (ST) is one of the most common and yet most unclear of otologic symptoms.(1-4) ST can accompany any type of hearing loss including both sensorineural as well as conductive hearing loss, and may originate from any part of the auditory pathway.(1,5) Treatment of ST must be primarily directed to the basic illness diagnosed after a thorough general ear-nose-throat and neurologic evaluation.(6) Severity of ST is evaluated both objectively, by determining the pitch and intensity of the tinnitus,(7) and subjectively as described by the patient. Because of the relatively high incidence of ST and in some patients, the severe personal reaction to it, many different treatments have been suggested, but generally only small to moderate success has been achieved in reducing tinnitus and its consequences, if any at all.(8) In this study we examined the effect of two treatment modalities: amitriptyline hydro-chloride and biofeedback.

Journal Article↗

PubMed1989

Neuropsychological and behavioral sequelae of amitriptyline overdose in infancy.

This study reports on the neuropsychological and behavioral problems of a 3(1/2) year-old boy who was poisoned by his Nanny with a massive dose of amitriptyline hydrochloride subsequent to a period of supranormal development. At the age of 8 months, the child was discovered at home in respiratory distress (he was "blue and not breathing"). Blood gases and toxin screens revealed a serum level of 1065 ng/ml for amitriptyline. The parents have reported a series of serious behavioral and emotional problems since this incident. Neuropsychological data gathered recently at the age of 3(1/2) years indicated a variety of nonfocal signs. Language development, serial processing skills, and attentional mechanisms showed the greatest degree of impairment.

Journal Article↗

PubMed1987

Migraine prophylaxis. A comparison of propranolol and amitriptyline.

The comparative efficacy of propranolol and amitriptyline in the prophylaxis of migraine headache was studied in 30 patients in a double-blind, placebo-controlled, crossover design. Headache response to medication was measured monthly by compilation of headache scores derived from quantitative data recorded by patients in a daily diary; at each visit, Zung and Hamilton tests for depression and the Spielberger state test for anxiety were performed. In the absence of clinical toxicity at monthly visits, the decision to maintain the current dose or raise it was made by a computer, which compared current headache score with that of the previous month. Both drugs were superior to placebo. Neither drug was superior to the other. The effectiveness of neither drug correlated with a decrease in anxiety or depression demonstrated by psychological testing.

Adult↗

PubMed1980

Amitriptyline once daily vs three times daily in depressed outpatients.

Two dosage schedules of amitriptyline hydrochloride, once daily vs three times daily, were compared in a group of 124 nonpsychotic depressed outpatients. After four weeks of treatment, patients on the once daily schedule had improved significantly more than patients receiving multiple doses on both physician and patient measures. The two groups did not differ in their attrition rates nor in reporting of side effects. Since treatment response to the tricyclic antidepressants is often delayed, once-daily dosage seems to offer a distinct advantage over more conventional multiple doses in depressed outpatients.

Adjustment Disorders↗

PubMed1982

Response to phenelzine and amitriptyline in subtypes of outpatient depression.

Outpatients with depression and mixed anxiety-depression were treated for six weeks with phenelzine sulfate, amitriptyline hydrochloride, or placebo in a controlled trial. Both active drugs were superior to placebo and were closely comparable in efficacy. Interactions were examined between drug response and classifications based on three different usages of the term atypical depression: additional anxiety or phobic symptoms, atypical functional shift, and nonendogenous depression. Some additional related classifications were also included. There was a tendency for phenelzine to have stronger effects in patients with additional anxiety and without evidence of chronic characterological depression. However, interactions were relatively few. These findings suggest that the two classes of antidepressant affect similar clinical subgroups within the outpatient depressive spectrum, with only relatively weak differences.

Adult↗

PubMed1985

Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression.

Five hundred four outpatients suffering from a major depressive episode were randomly assigned to receive either amitriptyline, doxepin, alprazolam, or placebo. The study was conducted in three treatment centers during a six-week period. All three active medications produced significantly more clinical improvement than did placebo, irrespective of the patient's initial anxiety, depression, and psychomotor retardation and irrespective of the patient's assignment to various subtypes of depression, including the DSM-III melancholia subtype. Compared with placebo, sedation was reported more frequently with all three medications, whereas anticholinergic effects were reported more frequently only for the two tricyclic antidepressants, but not for alprazolam.

Adult↗

PubMed1985

Treatment of depression with cognitive therapy and amitriptyline.

Thirty-three outpatients with primary nonbipolar depression received individual treatment with either cognitive therapy alone (n = 18) or cognitive therapy plus amitriptyline hydrochloride pharmacotherapy (n = 15). All patients were treated according to a protocol specifying a maximum of 20 sessions during a 12-week period. Both groups showed statistically significant and clinically meaningful decreases in depressive symptoms. No differences emerged between the two groups in terms of the magnitude of the decrease in depressive symptoms. The addition of tricyclic antidepressant medication did not improve the response obtained by cognitive therapy alone, during the short-term treatment phase. Although there was a nonsignificant trend suggesting greater stability of gains for the combined treatment at a one-year follow-up, the patients had more therapy during the follow-up period. There was no evidence of any negative interaction between cognitive therapy and pharmacotherapy, although evidence for any positive additive or interactive effect was meager.

Adult↗

PubMed1996

A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia.

OBJECTIVE: To study the effect of fluoxetine (FL) and amitriptyline (AM), alone and in combination, in patients with fibromyalgia (FM). METHODS: Nineteen patients with FM completed a randomized, double-blind crossover study, which consisted of 4 6-week trials of FL (20 mg), AM (25 mg), a combination of FL and AM, or placebo. Patients were evaluated on the first and last day of each trial period. Outcome measures included a tender point score, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) scale, and visual analog scales (VAS) for global well-being (1 completed by the physician and 1 by the patient), pain, sleep trouble, fatigue, and feeling refreshed upon awakening. RESULTS: Both FL and AM were associated with significantly improved scores on the FIQ and on the VAS for pain, global well-being, and sleep disturbances. When combined, the 2 treatments worked better than either medication alone. Similar, but nonsignificant, improvement occurred in the BDI scale, the physician global VAS, and the VAS for fatigue and feeling refreshed upon awakening. Trends were less clear for the tender point score. CONCLUSION: Both FL and AM are effective treatments for FM, and they work better in combination than either medication alone.

Adolescent↗

PubMed1998

On-line nonaqueous capillary electrophoresis and electrospray mass spectrometry of tricyclic antidepressants and metabolic profiling of amitriptyline by Cunninghamella elegans.

An on-line nonaqueous capillary electrophoresis-electrospray mass spectrometry (ESI-MS) technique was developed using a commercial ion spray interface. The nonaqueous capillary electrophoresis ESI-MS system was used to profile tricyclic antidepressants of similar structures and mass-to-charge ratios. We found that pure methanol can be used as a sheath liquid to obtain stable ion spray from nonaqueous capillary electrophoresis. The flow rate of the coaxial nebulizing gas affected baseline signals, separation efficiency, and migration times. Other nonaqueous capillary electrophoresis operating conditions and electrospray parameters were optimized for enhanced baseline separation and high sensitivity detection. The effect of sample stacking on separation and detection was evaluated. The calculated detection limits were approximately 3 pg injected onto the capillary. ESI mass spectra of tricyclic antidepressants from a single quadrupole MS were obtained and elucidated. The information was used to propose fragmentation pathways of the tricyclic antidepressants. The method was also used to analyze the metabolites of amitriptyline produced by the fungus Cunninghamella elegans. Sixteen metabolites were detected and most of them were tentatively identified as demethylated and/or hydroxylated, and/or N-oxidized products.

Amitriptyline↗

PubMed1975

Decomposition of amitriptyline hydrochloride in aqueous solution: identification of decomposition products.

The decomposition of amitriptyline hydrochloride upon autoclaving in a buffered solution (pH 6.8) was investigated. Three major decomposition products [3-(propa-1,3-dienyl)-1,2:4,5-dibenzocyclohepta-1,4-diene, dibenzosuberone, and 3-(2-oxoethylidene)-1,2:4,5-dibenzocyclohepta-1,4-diene] were detected and identified by chromatographic and spectroscopic techniques. Evidence is presented that the latter two compounds are formed by further oxidation of 3-(propa-1,3-dienyl)-1,2:4,5-dibenzocyclohepta-1,4-diene, and a possible decomposition pathway is outlined.

Amitriptyline↗

PubMed1977

Factors influencing decomposition rate of amitriptyline hydrochloride in aqueous solution.

The degradation rate of amitriptyline hydrochloride in buffered aqueous solution containing various additives was determined. The oxidation was a free radical-mediated process, and the rate was accelerated by the presence of metal-ion contaminants. Glass ampuls, particularly amber ones, in which the solutions were stored were the major source of these contaminants. Edetate disodium stabilized the solution, but the primary antioxidants propyl gallate and hydroquinone were less effective. Sodium metabisulfite accelerated the decomposition, and it is postulated that there was direct attack by metabisulfite at the olefinic double bond in the drug molecule.

Amitriptyline↗

PubMed1978

Quantitative determination of amitriptyline in blood.

An assay was developed and standardized for amitriptyline and its hydroxylated tertiary amine metabolites in blood and other biological tissues. This method is capable of determining 5--15 ng of these compounds/ml and is based on reacting the drug as base with 9-bromomethylacridine to form a quaternary product which, on photolysis, yields fluorescence in a stoichiometric fashion. The precision of the method is usually around +/-5%.

Amitriptyline↗

PubMed1980

NMR spectral study of proton transfer in amitriptyline hydrochloride--chlordiazepoxide hydrochloride combinations in dipolar aprotic solvent.

The singlet resonance due to the two equivalent methyl groups of amitriptyline hydrochloride in dimethyl sulfoxide-d6 solution changed into a doublet with the addition of chlordiazepoxide hydrochloride. A spin decoupling experiment revealed that the double originated because of the emergence of observable spin--spin coupling between the tertiary amine proton and the methyl groups. The phenomenon was interpreted to be due to the nature of proton transfer caused by the relative magnitudes of the basicities of the amines in these compounds, which were determined by the inductive and steric effects of the substituents, leading to the formation of hydrogen-bonded ion-pairs in the aprotic diluent. The enthalpy of the exchange process was 6.4 +/- 0.5 kcal/mole.

Amitriptyline↗

PubMed1992

Differential effects of amitriptyline on sudomotor, cardiovagal, and adrenergic function in human subjects.

Tricyclic antidepressants, especially amitriptyline (AMI), are widely used by patients who require tests of autonomic function. AMI effects autonomic function, but its quantitative and differential effects are not known. We prospectively evaluated the effect of AMI on sudomotor (M3 receptor), cardiovagal (M2) and adrenergic functions in 6 subjects, aged 20-40 years before, during, and 48 hours after AMI 75 mg/d. M3 receptor function was evaluated using QSART (quantitative sudomotor axon reflex test) recordings from four sites, M2 receptor function from cardiovagal studies [HR response to deep breathing (HRDB) and the Valsalva ratio (VR)], and adrenergic function from an analysis of beat-to-beat BP responses to tilt and the Valsalva maneuver. Plasma AMI was determined from blood samples obtained within 2 hours of autonomic testing. QSART volume was reduced by 47% by AMI (P = 0.01), and recovered to 81% of baseline following a 48-hour washout. HRDB was unaffected by AMI (P > 0.05). VR was increased by 10% (NS) with AMI and by 14% (P < 0.05) with washout. The percent change in hemodynamic parameters by AMI were: orthostatic reduction in SBP, 62% (NS); orthostatic HR increment, 66%, (P = 0.03); and phase IIe SBP decrement, 665%, (P = 0.02). We conclude that AMI in the moderate doses used, resulted in greater inhibition of M3 than M2 receptors. The BP, HR, and beat-to-beat BP alterations likely reflect adrenergic inhibition resulting in a reduction in effective plasma volume. A washout of 48 hours is adequate for muscarinic but not adrenoreceptors.

Adult↗

PubMed1993

Amitriptyline inhibits neurite outgrowth in chick cerebral neurons: a possible mechanism.

Previous studies showed that amitriptyline (AMI), a tricyclic antidepressant, inhibited neurite outgrowth from chick embryonic cerebral explants and inhibited adenylyl cyclase activity in cerebral membrane preparations. In the present study, we have investigated the possibility that AMI may have additional effects on cellular metabolism and signal transduction that underlie AMI-mediated inhibition of neurite outgrowth. In vitro, AMI inhibited phospholipase C in a dose- and GTP-dependent manner in membranes from 8-day-old chick forebrain. Brain homogenates from 8-day-old chick embryos, treated in vivo for 6 days with AMI (20 micrograms/g/day), showed significant reductions in (1) phosphorylation of two polypeptides (49 and 105 kD), and (2) levels of three polypeptides (43, 53, and 92 kD). Western blots showed that the 43- and 53-kD polypeptides corresponded to actin and tubulin, respectively. Diolein and dilinolein, potent activators of protein kinase C, stimulated neurite outgrowth and reversed the inhibitory effects of AMI. Sphingosine, a protein kinase C inhibitor, significantly inhibited neurite outgrowth and eliminated the stimulatory effects of diolein and dilinolein on neurite outgrowth. These data suggest that AMI-mediated inhibition of neurite outgrowth involves multiple effects on cellular metabolism and signal transduction. A hypothesis consistent with our data is that AMI interferes in some manner with the action of G proteins in the signal transduction cascade.

Adenylyl Cyclases↗

PubMed1994

Effect of amitriptyline on the analgesia induced by adrenal medullary tissue transplanted in the rat spinal subarachnoid space as measured by an experimental model of acute pain.

The effect of short and long term amitriptyline (AMI) treatment on the analgesia induced by adrenal medullary autotransplant into the subarachnoid space was investigated in rats. For this purpose, two experiments were carried out. In the first one, the rats were chronically treated for 28 days after transplantation. In the second experiment, rats were treated for 28 days starting 28 days after surgery. Before starting the experiments, basal levels were tested. Tail-flick latencies were checked at Day 4 and Day 28 in the first experiment and at Day 28 and Day 56 in the second. AMI itself did not induce any tail-flick modification after 28 or 56 days. However, it increased the transplantation-induced analgesia at Day 28 in the first experiment and at Day 56 in the second. These results are interpreted in the sense of the ability of AMI to enhance the effects of both monoamine and opioids previously released by the transplantation.

Acute Disease↗

PubMed1988

Trazodone in late life depressive states: a double-blind multicenter study versus amitriptyline and mianserin.

Seventy five elderly depressed in-patients, ages ranging from 60 to 83 years, diagnosed as Major Depression according to DSM III were treated, under double-blind conditions, with 75 mg Amitriptyline (AMI) (26 patients), 60 mg Mianserin (MIA) (24 patients) or 150 mg Trazodone (TRZ) (25 patients) p.o. for 5 weeks. There were no differences in the clinical outcome between the three groups of patients at the end of the trial, with a significant amelioration (P less than 0.01) at the Hamilton Rating Scale for Depression and Geriatric Depression Scale. TRZ showed a significantly lower incidence of side effects compared to MIA and AMI. Atypical antidepressants, including TRZ, seem more suitable for treating elderly depression than the first generation antidepressants on the basis of risk/benefit ratio considerations.

Aged↗