Amitriptylinoxide

Abstract: Plasma drug levels and urinary metabolites were measured in a volunteer for 28 h after ingestion of amitriptyline hydrochloride or amitriptyline N-oxide (amitriptylinoxide) equivalent to 100 mg of amitriptyline base. The N-oxide initially produced high plasma levels and 15% of the dose was excreted unchanged within 14 h. From comparison of the metabolite excretions, it can be concluded that about 70% of the dose was reduced at the N-oxide group, while comparison of the areas under the plasma group, while comparison of the areas under the plasma level-time curves for amitriptyline pointed to a 55% reduction to the amine. Less drowsiness was experienced after ingesting the N-oxide, and there was no depressive mood.

Abstract: In a double-blind trial, 32 patients with endogenous or neurotic depression requiring drug treatment in hospital were randomly allocated to a four-week treatment with amitriptylinoxide or amitriptyline. The initial dosage was, in most cases, 60 mg b.i.d. for both drugs. During the first week of treatment, the dose was increased to a maximum of 300 mg/day with amitriptylinoxide and to 240 mg/day with amitriptyline, depending on tolerability and clinical impression. This dose was then maintained, if possible, throughout the following three weeks. During this period the mean dose of amitriptylinoxide was 167 +/- 8 mg/day, that of amitriptyline 166 +/- 8 mg/day. Seven of the 32 patients (three in the amitriptylinoxide and four in the amitriptyline group) discontinued the trial. Therapeutic efficacy was assessed by means of the AMDP system (scale 4), HAMD total scale, 4 HAMD subscales, and DSI and Bf-S scales. Tolerability was assessed using the AMDP system (scale 5) and a list of side-effects often associated with antidepressive drug treatment. With regard to therapeutic efficacy, no differences were noted between the two drugs except on the DSI scale. In contrast, there was a significant difference in tolerability--both in terms of the vegetative syndrome (AMDP) and the sum of side-effects--in favour of amitriptylinoxide.

Abstract: Eleven healthy volunteers were examined in a pharmacokinetic study. After oral administration of 50 mg amitriptylinoxide or 50 mg amitriptyline the plasma levels of amitriptylinoxide and its main metabolites amitriptyline and nortriptyline were investigated over 24 hours. The results indicate that amitriptylinoxide is more rapidly absorbed than amitriptyline and eliminated with a mean half-life of 1.5 hours. The change with time in the levels of amitriptyline formed from the oxide is similar to that of amitriptyline after ingestion of amitriptyline. However, the plasma concentration of amitriptylinoxide, reflected by the area under the time curve (AUC), exceeds that of its metabolite amitriptyline twelvefold.

Abstract: In a cross-over design, six healthy volunteers received 50 mg amitriptylinoxide (AT-NO) IV and orally and 50 mg amitriptyline (AT) IV. Urine was collected completely for 8 h and occasionally up to 48 h. In addition, five patients each under treatment with AT-NO or AT for tension headache collected 24-h urine samples. The following compounds were analysed by HPLC: AT-NO, E- and Z-10-hydroxy-AT-NO (E- and Z-10-OH-AT-NO), free and conjugated AT, E- and Z-10-OH-AT and their mono- and didemethylated analogues, and 2-OH-nortriptyline (2-OH-NT). Unchanged AT-NO in urine accounted for an average of 34% and 22% of the single IV and oral doses, respectively, and for 28% in continuous therapy, with a further 8–9% being excreted as E- and Z-10-OH-AT-NO. The remaining part was converted to the same metabolites as was AT. In the steady state the measured compounds accounted for 74% and 77% of the daily AT-NO and AT doses, respectively. The renal plasma clearance of AT-NO varied between 75 and 265 ml/min in the six volunteers. Tubular secretion must play an important part in the renal excretion of AT-NO.