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SUMMARY Methods: The retrograde spread of two budesonide enema formulations with different viscosities was investigated. The study design was open, randomized and two-period crossover. Three female and two male patients (age range: 35-45 years) with distal ulcerative colitis or proctitis participated. Both enema formulations contained a dose of 2 mg budesonide/ 100 mL. An unabsorbable radioactive marker ( 99mTc-labelled human serum albumin microcolloid) was added to the enema just before administration. All doses were given in the evening with the patients lying in a supine position during the whole investigation. The intestinal spread was followed for 8 h using scintigraphic imaging. Plasma samples for budesonide assay were taken during the 12 h after administration of the low viscosity enema. Results : Budesonide plasma levels were measurable for up to 4-6 h. C,,, was 2.5 nmol/L (range: 0.9-4.5 nmol/L) and was attained in 1.5 h (range 1-3 h). The patients had no difficulty in retaining the enemas. There was a statistically significant difference in spread between the low and high viscosity enema. The low viscosity enema spread over an area situated between the rectum and the splenic flexure. The spread occurred mainly in the first 15 min after administration. In contrast, the high viscosity enema, in most cases, spread only over a minor part of this area and the rate and extent of spreading was also more variable with this formulation. Conclusion: The spread of a low viscosity enema appears to be well suited for the treatment of proctitis and distal colitis.

NXY-059 is a free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. Acute ischemic stroke patients receiving NXY-059 may also be exposed to diuretics for treatment of heart failure or hypertension. NXY-059 and furosemide are partly eliminated by active tubular secretion via an organic anion transporter. This double-blind, randomized, crossover, placebo-controlled study investigated whether an infusion of NXY-059 (15 mg/mL) during 12 hours affects the diuretic and saluretic effects of a 30-mg intravenous bolus dose of furosemide (10 mg/mL) administered after 6 hours' infusion, in 13 male and 11 female healthy subjects. The net increase in urine volume and sodium excretion in the interval of 6 to 12 hours was 4.15 L and 178 mmol/L, respectively, during NXY-059 treatment (P = .93) and 4.34 L and 190 mmol/L, respectively, during placebo treatment (P = .54). NXY-059 reduced the renal clearance of furosemide by 19% (P = .019), and furosemide reduced the renal clearance of NXY-059 by 8% (P = .005). NXY-059 was well tolerated.

The cerebrospinal fluid (CSF) and plasma levels of demethylchlorimipramine (DMCI) were determined during treatment of depression or obsessive-compulsive disorders with chlorimipramine. In 18 patients the mean CSF/plasma ratio of DMCI was 2.6% +/- 0.7 SD with fourfold variation (1.1% to 4.0%). In spite of this variation, the levels in CSF and plasma at steady state correlated closely (r = 0.91; p less than 0.001). With equilibrium dialysis for the determination of the protein binding of DMCI, a much higher free fraction was found in patients (8.0 +/- 1.6%) and in control subjects (8.2 +/- 1.4%). It was shown that part of the plasma binding capacity was lost during the incubation. Results obtained by ultrafiltration (3.9 +/- 1.0% unbound drug) were closer to the in vivo results, but this method also had disadvantages; much of the drug was absorbed on the ultrafiltration dialysis membrane. Our results suggest that there is a need for care in the selection of a technique for studies of drug protein binding.

The protein binding of two basic drugs, alprenolol and imipramine, and the acidic drug, naproxen, was determined in plasma obtained from 23 healthy subjects. A 2jold variation was found between individuals in the free fraction of the two bases, while the range was even greater with naproxen. The free fraction correlated with the plasma concentration of ai-acid glycoprotein for alprenolol (r = -0.75, p 0.1). This confirms recent experiments which showed that isolated ai-acid glycoprotein avidly bound both alprenolol and imipramine. Drug binding, however, did not correlate with albumin concentration, although experiments with isolated albumin demonstrated its unusually high affinity for naproxen.

Protein binding of salicylate was studied by equilibrium dialysis at 37 degrees C in plasma from uremic patients and healthy subjects. The protein binding was considerably lower in the uremic plasma at all salicylate concentrations studied (14 to 1,400 mug/ml). Scatchard plots of the data were computer-analyzed assuming binding to the classes of binding sites. According to this analysis, the binding to the class of primary binding sites was considerably decreased in the uremic plasma. In addition to the effect of the uremic state, the binding was considerably decreased at high therapeutic plasma levels and at low albumin levels. The combined effect of two or three of these factors may lead to unexpectedly high unbound fractions of salicylate, which should be considered in the monitoring of plasma salicylate levels in patients.

With the intention of studying the fate of transplacentally transferred diphenylhydantoin (DPH, phenytoin) in the newborn infant, a mass fragmentographic analytic method has been developed, in which deuterium-labeled DPH is used as internal standard. The analytic procedure permits precise determinations of DPH in 100 µl plasma samples in concentrations down to 0.01 µg per milliliter. Seven newborn infants of epileptic mothers treated with DPH throughout the pregnancy were studied during the first 4 to 9 days of life. The rate of plasma disappearance of DPH in the newborn infants was of the same order of magnitude as previously reported in adults. The initial parts of the plasma concentration curves indicated zero-order disappearance of DPH. Nursing did not seem to affect the rapid plasma level decline in the babies until extremely low concentrations (0.1 p.g per milliliter) were reached. The arr,wunts of unchanged drug excreted in the urine were inSignificant. It is therefore concluded that babies born by mothers treated chronically with DPH are able to metabolize this drug effectively immediately after birth.

The effect of intravenously administered ampicillin on plasma levels and renal clearance of enprofylline was investigated in seven young and six elderly volunteers. On one occasion, each subject received 2 g of ampicillin intravenously, and serum concentrations of ampicillin were followed for 4 hours. On a separate occasion, a loading infusion of enprofylline was administered over 60 min., aiming at a plasma level of 2 micrograms/ml, and followed by a maintenance infusion. During this an infusion of 2 g of ampicillin was given for 10 min., and subsequently, renal clearance and plasma levels of enprofylline were followed for 4 hours. Plasma enprofylline levels increased significantly in the subjects after ampicillin infusion, but the effects on renal clearance of enprofylline were not statistically significant. The magnitude of the effects on enprofylline plasma levels and renal clearance from high doses of ampicillin do not suggest that interaction with beta-lactam antibiotics will be a serious problem for patients on enprofylline treatment.

After intravenous administration of desmethylimipramine and nortriptyline to dogs, the excretion of unchanged drug in urine or gastric juice was found to be of little quantitative importance. The renal excretion was pH dependent, indicating nonionic diffusion between blood and urine. The urinary excretion of desmethylimipramine or nortriptyline given in therapeutic doses to depressed patients was also shown to be pH dependent. At a steady-state plasma level of the antidepressant drugs, less than 5 per cent of the daily dose was excreted unchanged through the kidney. These data are discussed in relation to the treatment of tricyclic drug intoxications.

The inhibitory effect of nortriptyline (NT) on the neuronal uptake of radio labeled norepinephrine (NE) was studied with the use of the rat iris preparation in Krebs-Ringer solution or human plasma. When added to the incubation medium, NT inhibited the uptake of NE approximately ten times as effectively in buffer as in human plasma within the tested concentration range of NT (10−8 to 10−6M). This result is in good agreement with the 94 per cent binding (at NT concentration of 1.1 10−6M) obtained by the ultrafiltration method. Plasma from patients treated with NT also inhibited the uptake of NE. Correlation between the inhibitory effect and the “endogenous” plasma level of NT in the 14 patients studied was significant (p < 0.001). When NT was added in different concentrations to control plasma the inhibitory effect observed was close to that obtained with patient plasma containing the same “endogenous” concentration of NT.