Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism

1   The interaction between triazolam and two antifungal agents, fluconazole and terbinafine, was investigated in a double-blind, randomized crossover study of three phases.
2   Twelve healthy young volunteers received 100  mg fluconazole, 250  mg terbinafine or placebo orally once a day for 4 days. On day 4 they took a single 0.25  mg dose of triazolam. Plasma samples were collected and pharmacodynamic effects were measured up to 17  h after the intake of triazolam.
3   Fluconazole increased the area under the triazolam concentration time-curve more than twofold ( P <0.001) and prolonged the elimination half-life of triazolam nearly twofold ( P <0.001). The peak concentration of triazolam was also increased significantly ( P <0.05) by fluconazole.
4   During the fluconazole phase pharmacodynamic effects of triazolam (e.g. digit symbol substitution test, body sway and drowsiness) were enhanced significantly (P<0.05) when compared with the placebo phase.
5   Terbinafine did not change significantly the pharmacokinetics or pharmacodynamics of triazolam.
6   Care should be taken when triazolam is prescribed to patients using fluconazole. Although the interaction is not as strong as that of triazolam with ketoconazole or itraconazole, it is clinically significant. Triazolam and probably other drugs metabolized by CYP3A4 can be used in normal doses with terbinafine.     

The impact of HLA-DR compatibility on cadaver kidney graft survival in a prospective study with special emphasis on the quality of typing

The survival data of 151 consecutive cadaver kidneys transplanted by the two transplantation centres of Copenhagen from September 1, 1980 to September 30, 1982 with an observation period of at least 3 months have been analyzed. The HLA-DR types could not be established in 4 out of 130 donors. In most of the analyses only the well-defined antigens DR1, 2, 3, 4, 5, 7, and w8 were included. Inclusions of the DRw6, w9, and w10 antigens in the matching did not change the results. The one-year graft survival (GS) was 72.1% for 97 HLA-DR compatible kidneys as compared to 41.4% for 49 incompatible kidneys (p = .0007); this difference remained highly significant when stratified for the recipient status of pretransfusion, risk, and age. Non-transfused recipients had a fairly good GS but had received significantly better matched kidneys than the remaining recipients. The transfusion "effect" became barely significant (p = .054) when stratified for DR. There was no significant influence of donor or recipient DRw6-type as defined in this study. The GS was not significantly influenced by HLA-A, B matching, recipient antibody status, B cell cross-matches, transplant, or donor centre. Special efforts were made to assign the HLA-DR phenotypes of the recipients and donors as accurately as possible. In 39 cases, there was a discrepancy between the result of the acute DR-typing of the donor and the final result based on subsequent typings. The acute DR match had no influence on GS in these recipients whereas the final match had a significant influence in the same group, which in a way comprise a randomized trial. In the total material, the acute DR match still showed an influence on GS, but the significance decreased by a factor 20. This illustrates how the quality of DR typing may influence the results of the analyses. The overall GS (62.5%) was significantly (p = .05) better in this series than that (48.2%) in our preceding series, but it is uncertain whether this is due to better matching alone.     

Topical betamethasone 17-valerate is an anticorticosteroid in the rat

In the oxazolone-induced delayed hypersensitivity inflammation in the rat ear, betamethasone 17-valerate, in contrast to other topical corticosteroids, is incapable of suppressing oedema. When given in combination with triamcinolone acetonide, betamethasone 17-valerate competitively anta-gonizes the anti-inflammatory action of the active steroid. When tested in the mouse, betamethasone 17-valerate behaved as an anti-inflammatory agent 15 and 80 times as potent as betamethasone and hydrocortisone respectively. In an in vitro lymphocyte culture system in which preincubation with corticosteroids prevents subsequent phytohaemagglutinin induced DNA synthesis, betamethasone 17-valerate was less active than even hydrocortisone when rat lymph node cells were used, but with human cell preparations it was more potent than either hydrocortisone or betamethasone. Betamethasone 17-valerate behaves uniquely in the rat as an anticorticosteroid; in mouse and in man the compound behaves as a normal corticosteroid.     

Confirmation of the primary structure of thymosin α1 by microsequence analysis of limited acid and enzymatic hydrolysis fragments

The primary structure of the 28-peptide thymosin α₁ as determined by Goldstein et al. (1) has been confirmed by independent procedures. Limited dilute acid digestion generated a 26-peptide and a 22-peptide both extending to the C-terminal and lacking the N-terminal blocking group. A combination of Edman microsequencing, carboxypeptidase Y and thermolysin digestion, and fast atom bombardment mass spectrometry was used.     

Sudden Death in Pacemaker Patients

Of 264 pacemaker patients who died within 27.6 ± 21 months following pacemaker implantation, 36 (13.6%) died suddenly. There was no difference between them and the remaining patients in terms of age, sex, indications for pacing, type of pacemaker used, and interval between pacemaker implantation and death. On autopsy, all but one patient were found to show severe three-vessel disease without evidence of acute myocardial infarction. The cause of death would thus be compatible with malignant ventricular tachycardia.     

Thermal Catheter Disruption During Closed-Chest Radiofrequency Ablation of the Atrioventricular Conduction System

Radiofrequency ablation of the atrioventricular conduction system was attempted in a 63-year-old man with drug refractory atrial fibrillation. A total of 5 radiofrequency pulses (750 kHz, power setting: 25-50 W, pulse duration: 9-20 sec) were delivered in a unipolar fashion via the distal electrode of a 7 Fr bipolar electrode catheter without induction of permanent AV block. No direct measurements of current (I) and voltage (U) were made. During the fifth pulse catheter disruption occurred at the interface of the shaft and the proximal electrode. Inspection of the catheter shaft revealed carbonized insulation material indicating overheating of the catheter tip. Overheating was presumably due to an impedance rise with unrecognized clot formation on the distal electrode. This led to progressive melting of insulation material during repeated radiofrequency applications and short circuiting of current flow to the proximal ring electrode that resulted in catheter disruption. This case report is the first to describe a serious complication of radiofrequency ablation. The complication might have been prevented by measurements of U and I, reflecting changes in impedance or by measurements of catheter tip temperature (T). It is concluded that measurements of U, I, and/or T are necessary to control the coagulation process thereby reducing the risk of serious complications during transcatheter radiofrequency ablation.