Antisecretory activity of human, dog, and rat metabolites of fenoctimine.

Fenoctimine (1a), a nonanticholinergic inhibitor of gastric acid secretion in dogs and rats, was evaluated as a gastric antisecretory agent in humans. In humans it exhibited weak antisecretory activity and caused anticholinergic-like side effects such as dry mouth and nasal passages. Studies of the metabolic fate of fenoctimine in humans, dogs, and rats provided structures of the resultant metabolites. These were synthesized and tested for antisecretory and anticholinergic activity. The human metabolites were all less active than fenoctimine as antisecretory agents, and some displayed significant anticholinergic activity. These results suggest that the unexpectedly weak effect of fenoctimine as a gastric antisecretory agent in humans, as well as anticholinergic effects, may be due to its extensive metabolism, which is different from that seen in dog and rat.

Effects of dialysis membrane on intradialytic vancomycin administration.

STUDY OBJECTIVE: To quantify the influence of hemodialyzers on vancomycin removal when the drug was infused during hemodialysis. DESIGN: Prospective, controlled, crossover study with three arms. SETTING: A university-affiliated medical center. PATIENTS: Eight subjects receiving outpatient hemodialysis. INTERVENTIONS: The three treatment arms were vancomycin 1000 mg infused after dialysis was completed (control), and the same dosages infused during the last hour of hemodialysis with a cellulose triacetate (CT) and a cellulose acetate (CA) hemodialyzer. MEASUREMENTS AND MAIN RESULTS: The areas under the curve from time zero to 44 hours (AUC0-44 hrs) for the three study arms were significantly different (p < 0.05), with the mean vancomycin AUC0-44 hrs being significantly lower when administered during CT and CA dialysis (73.7% and 87.2% of control; p < 0.05 vs control). The mean vancomycin peak concentration achieved during CT dialysis was significantly lower than for the CA and control arms (20.5, 23.9, 27.0 mg/L, respectively). Forty-four-hour postinfusion concentrations were similarly lower. CONCLUSION: Clinicians should recognize that the composition of the hemodialyzer significantly influences vancomycin serum concentrations when the drug is administered during hemodialysis.

Vancomycin mass transfer characteristics of high-flux cellulosic dialysers.

BACKGROUND: In comparison to conventional haemodialysis membranes, highly permeable membranes allow a broader spectrum of solute removal, including enhanced elimination of vancomycin (1448 Daltons). However, the mass transfer characteristics of vancomycin removal by highly permeable membranes have not been adequately assessed. An understanding of vancomycin's predominant dialytic mass transfer mechanism under a given set of operating conditions, including dialyser type and flow rates, may permit more accurate dosing of the drug. METHODS: We performed a mass transfer analysis of vancomycin removal by a high-flux dialyser, cellulose triacetate (CT). In a cross-over fashion with a 3-week washout between treatments, eight subjects received vancomycin 1000 mg (1) during the last hour of CT haemodialysis; or (2) after dialysis. Serial urea and vancomycin serum concentrations were used to assess dialytic removal. RESULTS: Dialysis removed 26.2% (mean; range 16-44%) of the administered vancomycin dose. While vancomycin removal and (Kt/V)urea were directly correlated (r = 0.88; P < 0.005), no correlation was observed between vancomycin removal and weight-normalized ultrafiltration rate. CONCLUSIONS: These findings suggest that for the CT dialyser and dialysis operating conditions employed in this study, vancomycin clearance was primarily mediated by diffusion. As such, these data challenge the general concept that convection is primarily responsible for the removal of solutes in the same molecular weight class as vancomycin during high-flux dialysis.