The circadian variation of clinical pharmacokinetics of tacrolimus was studied using 16 adult renal transplant recipients 1 month after the operation. The recipients were administered tacrolimus twice a day (9 a.m. and 9 p.m.), and whole-blood samples were obtained just prior to and 1, 2, 3, 6, 9, and 12 hours after oral administration. Histological specimens of transplant kidney were collected by an allograft core biopsy on day 28 after the transplantation. There were no circadian changes in the area under the concentration-time curve (AUC0-12) (214 ng.h/mL during daytime vs. 223 ng.h/mL during nighttime) resulting from morning and night doses. A slight delay in mean residence time (MRT0-12) and time to the peak concentration (tmax) was found after night doses, but there was no statistical significance. Three patients (18.8%) had a clinical acute rejection (AR) episode 4 to 6 weeks after transplantation, and AUC0-12 at nighttime was significantly lower (18.4% on average) in patients with AR in comparison to those without AR. There was no statistical significance in maximum concentration (Cmax) or morning/night trough levels between patients with and without AR. In regard to the correlation between tacrolimus concentrations in each sampling time and AUC0-12, the morning trough concentrations were less predictable for daytime AUC0-12 (r2 = 0.125), but there was a weak correlation to nighttime AUC0-12 (r2 = 0.424). Tacrolimus concentrations at 2, 3, and 6 hours after the morning dose (C2, C3, and C6) had a good correlation against daytime AUC. The results of this study indicate that the variance on the clinical pharmacokinetics of tacrolimus between daytime and nighttime in renal transplant patients is not significant, while the lower nighttime AUC corresponded to the occurrence of AR.

The role of the pudendal nerves on the dynamics of micturition was studied using 16 decerebrated dogs. The voiding cycles were analyzed by pressure flow EMG and pressure flow plot studies under 3 conditions: control, after unilateral, and after bilateral pudendal nerve transection. In the control condition, highly reproducible reflex micturition with bladder contraction and spasmodic rhythmic sphincter contractions was demonstrated. Two patterns were noted following pudendal nerve transection: reflex micturition and overflow incontinence. Even though reflex micturition could be achieved in 9 out of 16 dogs after bilateral transection, there was decreased bladder emptying as well as absence of spasmodic rhythmic sphincter contractions. Overflow incontinence developed in the remaining 7 dogs (5 dogs after bilateral transection and 2 dogs after unilateral transection). It appears that the pudendal nerves play an important role in emptying the bladder of the dog.

Adrenergic influences on the voiding cycle were clarified by the modem urodynamic technique of pressure flow electromyogram study in 20 decerebrated dogs. A series of experiments were performed before and after hypogastric nerve transection. Similar experiments were done before and after pharmacologic blockade of a-and P-adrenergic receptors. In the control condition, reflex micturition occurred when a critical degree of filling was reached. After hypogastric nerve transection or administration of phentolamine or propranolol, reflex micturition still occurred. However, hypogastric nerve transection, phentolamine, and propranolol produced significant changes in the values of some urodynamic parameters. It appears that adrenergic function plays a definite role in the voiding cycle of the decerebrated dog by regulation of bladder and urethral smooth muscle activity.

A new video urodynamics to evaluate lower urinary tract function is presented. Video urodynamics was described originally as a combined radiographic and urodynamic monitoring. We describe certain modifications of original method, using the ultrasonotomographic method instead of the radiographic method. The urodynamic data and the simultaneous ultrasonotomography can be displayed through the display controller on the color display monitor. Our technique will be an extremely reliable method for the evaluation of lower urinary tract function.

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