Acyclovir kinetics after intravenous infusion.

The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.

Species differences in the disposition of acyclovir.

The disposition of acyclovir was investigated in several species. The drug was well distributed into all the tissues, including the brain, in mice and rats. Binding of acyclovir to plasma proteins was 36 percent or lower. After intravenous bolus dosing (20 mg/kg) in dogs, the plasma acyclovir concentration-time profile, determined by radioimmunoassay, showed a biphasic decline with a half-life in the elimination phase of 2.3 +/- 0.1 hours. The volume of distribution (Vd beta) of 1.2 +/- 0.2 liters/kg indicated distribution of drug into the tissues. Marked species differences were observed in the gastrointestinal absorption and biotransformation of acyclovir. Oral dosing produced better absorption in dogs and mice than in rats and rhesus monkeys. More than 95 percent of the radioactivity in the urine derived from a 14C-acyclovir parenteral dose was recovered as the unchanged drug in mice, rats, and dogs. Minor urinary metabolites were characterized by high-performance liquid chromatography as 9-carboxymethoxymethylguanine (CMMG) and 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. In other species--guinea pig, rabbit, and rhesus monkey--up to 40 percent of the radioactivity in the urine consisted of these metabolites.

Bradykinin-stimulated prostaglandin E2 production by endothelial cells and its modulation by antiinflammatory compounds.

Prostaglandin production was studied in cultures of pig aorta endothelial cells using radioimmunoassay, radiochromatography, and smooth muscle bioassay. PGE2 was produced in higher concentrations than other prostaglandins. Bradykinin produced a rapid dose-related stimulation of PGE2 production. These results provided the basis for establishment of a simplified test system for investigating new compounds which alter prostaglandin synthesis and might therefore affect inflammatory response. It was also observed that these endothelial cells do not metabolize prostaglandins via 15-hydroxyprostaglandin dehydrogenase.

A controlled evaluation of dermabrasion versus CO2 laser resurfacing for the treatment of perioral wrinkles.

Facial skin treatments with laser resurfacing, dermabrasion, and chemical peels were responsible for a significant portion of the 2.7 million cosmetic procedures performed in 1998. Perioral wrinkles are a common problem for which plastic surgical consultation is obtained. The aim of this study was to compare and quantify the advantages and disadvantages of laser resurfacing versus dermabrasion in the treatment of perioral wrinkles. Twenty female patients provided informed consent and participated in the study. Half of the perioral area was treated with dermabrasion and half was treated with the UltraPulse CO2 laser. The two procedures were compared using high-quality photographs; a biophysical evaluation of skin color, hydration, and mechanical properties; and patient evaluation of outcomes. Photographs were evaluated by 10 board-certified plastic surgeons who were blinded to the treatment methods. The laser treatment had a significantly higher erythema score at 1 month and a small but significantly greater improvement in perioral wrinkles at 6 months. Thirteen subjects selected the laser treatment as producing the best result, despite the greater intraoperative pain for this procedure. Biomechanical measurements suggest that the laser treatment produced a skin state more similar to skin in younger patients, presumably with higher levels and/or greater organization of the collagen and elastin. Patient preference was inferred from the resurfacing method that they would recommend to a friend. Although the laser was selected as the best result in a majority of cases, patient preference was equally distributed between the two treatments. The authors think that by studying and quantifying the biophysical changes that occur as a result of CO2 laser resurfacing, greater improvements in restoring actinic damage (e.g., wrinkles) can be achieved. Patients consider more than the objective skin changes from a resurfacing technique when making a recommendation to a friend.

The role of the intestinal tract in the elimination of carbon tetrachloride.

The target organ toxicity, mechanisms of toxicity, and metabolism of carbon tetrachloride (CCl4) have been studied extensively. However, there is a paucity of information concerning its elimination. Previous inhalation studies showed that a significant amount of 14C appeared in the feces of rats and monkeys exposed to 14CCl4. The nature of the compound(s) excreted in the feces has not been well characterized. Fecal excretion is a major route of elimination for many lipophilic compounds that are resistant to metabolism. A mechanism of excretion for these compounds is the direct exsorption from the blood to the lumen of the intestinal tract. The primary purpose of this study was to determine if fecal elimination contributes significantly to the elimination of CCl4. The secondary purpose was to determine the mechanism (biliary and/or nonbiliary, i.e., direct exsorption) of fecal elimination of CCl4 and/or its metabolite(s) in Sprague-Dawley rats. The results indicate that both biliary and nonbiliary mechanisms contribute to the fecal elimination of CCl4 following a single iv dose (1 mmol/kg), but this route accounts for less than 1% of the administered dose. The results also indicate that CCl4 is not eliminated unchanged in the feces following either acute treatment (iv or ip) or repeated inhalation exposures. Fecal elimination of CCl4 does not significantly contribute to the overall elimination of CCl4.

Effect of pyridine on the hepatic and pulmonary metabolism of 2-butanol in rat and rabbit.

Pyridine has been shown to be an effective inducer of the ethanol-inducible cytochrome P-450IIE1 in both liver and lung. The oxidation of 2-butanol by rat liver is inducible by chronic ethanol consumption. The purpose of this study was to determine the effect of pyridine on the hepatic and pulmonary metabolism of butanol. Comparisons were made between rat and rabbit. Acute pyridine treatment (200 mg/kg, ip) increased hepatic metabolism of 2-butanol in the rat twofold and in the rabbit threefold. The effect of pyridine on hepatic butanol oxidase is similar to the effect reported by other investigators for ethanol administered in the drinking water for 3 wk. Control rabbit pulmonary butanol oxidase activity was 10-fold higher than that in the rat. Pyridine decreased pulmonary butanol oxidase activity in the rabbit. The effect was demonstrated both in vitro and in the isolated perfused rabbit lung. Pyridine had no effect on pulmonary butanol oxidase activity in the rat.

Left ventricular growth in a patient with critical coarctation of the aorta and hypoplastic left ventricle.

An infant is presented who at birth met criteria consistent with hypoplastic left heart syndrome. He was followed clinically and by 11 weeks of age demonstrated substantial growth of the left ventricle. He underwent successful repair of coarctation of the aorta and continues to do well with moderate aortic stenosis. The difficulties of predicting left ventricular growth and function are discussed, and management options are reviewed.

The effect of pyridine on the in vitro and in vivo metabolism of ethyl carbamate (urethane) by rat and mouse.

Ethyl carbamate (EC, urethane) is a known carcinogen in laboratory animals. A genotoxic mechanism has been proposed which involves the bioactivation of EC to a reactive epoxide by the ethanol-inducible CYP2E1. The purpose of this study was to determine if pyridine (200 mg/kg i.p.), an inducer of CYP2E1, would increase the in vitro metabolism of EC and the in vivo binding of EC to cellular macromolecules. Treatment of rats or mice with pyridine increased hepatic microsomal metabolism of [14C-carbonyl]EC to CO2, but had little effect on pulmonary microsomal metabolism. The increase in hepatic metabolism was inhibited by the CYP2E1 inhibitor diethyldithiocarbamate, but not by the esterase inhibitor paraoxon, clearly indicating a role for this isozyme in hepatic metabolism of EC. In vivo, pyridine (200 mg/kg i.p.) administered 18 h prior to dosing with EC decreased the binding of [14C-ethyl]EC to cellular macromolecules. These data indicate that pyridine administration to rats and mice induces CYP2E1 metabolism of EC in vitro, but inhibits EC metabolism in vivo, perhaps by acting as an alternate substrate for CYP2E1.

Utilization statistics and diagnostic accuracy of a nonhospital-based positron emission tomography center for the detection of coronary artery disease using rubidium-82.

A retrospective analysis has been carried out to determine utilization and diagnostic accuracy of positron emission tomography of the heart with rubidium-82 at a nonhospital-based center. Utilization statistics were derived for the first 27 months of operation of the center from a total of 1,670 patients scanned. Diagnostic accuracy for detection of coronary artery disease was assessed using three readers, blinded to the clinical information, who read 225 rest and dipyridamole-stress scans of patients that had a coronary angiogram. Utilization statistics show that the center averaged 64 patients per month, 66% were males, 38% of the patients scanned had a coronary angiogram, 25% had a history of myocardial infarction, 12% had coronary artery bypass graft surgery, and 18% had percutaneous transluminal coronary angioplasty. Sensitivity was 82%, 96%, and 100% for myocardial regions perfused with greater than 67%, 84%, and 100% diameter stenosis, respectively. Specificity was 91% for all normal regions of the heart. Accuracy was 89%, 93%, and 93% for regions with greater than 67%, 84%, and 100% diameter stenosis, respectively. These results compare well with published results from major hospital based centers.

Limitations in prediction of gestational age and birth weight by ultrasonographic methods.

The index of predictability of estimated gestational age (EGA) and birth weight (BW) from biparietal diameter (BPD) was tested in 1333 normal pregnancies; 96% of the patients were black. The correlation BPD and actual weeks to delivery was 0.834, r2 =69.5%. Confidence limits were established and a nomogram for EGA was derived. Our nomogram and two similar ones were compared. The overall correlation between them was good, but that for specific BPD and EGA was not. In addition, our BPD values were smaller for corresponding gestational ages in other nomograms. The overall accuracy of estimated delivery date was +/- 1.6 weeks. We were not able to predict birth weight at all from a single, random BPD measurement. We have demonstrated the serious limitations that exist in the prediction of gestational age from previously established nomograms. We infer that this error is even greater when homogenous populations are so studied. We suggest that any published BPD-EGA or BPD-BW nomogram be given close, intensive statistical scrutiny, within the population studied, before it is used. When such scrutiny is not possible, serial sonographic determinations, or longitudinal use of growth charts, would be more acceptable.

The disposition of acyclovir in different species.

The absorption, distribution and biotransformation of the antiviral drug acyclovir were investigated in several species. Its oral administration resulted in better absorption and higher plasma levels in the dog and mouse than in the rat and rhesus monkey. Although more total drug was absorbed, the fraction of the oral dose of acyclovir absorbed declined with increasing doses of drug. When 14C-labeled acyclovir was given s.c. to mice and rats it was distributed into all the tissues examined, including the brain. In the dog, the drug was present in the cerebrospinal fluid, the aqueous humor and saliva after an oral dose. Binding of acyclovir to plasma proteins was less than 35%. In metabolism studies with radioactive acyclovir, high-performance liquid chromatography showed that 94 and 95% of the urinary radioactivity in mice and rats was unchanged acyclovir. Minor urinary metabolites were identified as 9-carboxymethoxymethylguanine and 8-hydroxy-9-(2-hydroxy-ethoxymethyl)guanine. There was no enhanced metabolism of the drug after its repeated daily administration to mice or dogs.

Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans.

The effects of probenecid on the pharmacokinetics and renal clearance of acyclovir were studied in humans. Acyclovir (5 mg/kg) was given as a 1-h infusion to three volunteers with normal renal function both before and after oral administration of probenecid (1 g). The kinetics were well described by a two-compartment open model with zero-order infusion. The mean acyclovir concentrations at all time points after 1.0 h from the end of acyclovir infusion following probenecid administration were statistically higher than the corresponding mean acyclovir concentrations following the acyclovir infusion without probenecid administration. In the absence of probenecid, the renal clearance (248 +/- 80 ml/min per 1.73 m2) accounted for 83% of the total clearance (300 +/- 69 ml/min per 1.73 m2) and was almost threefold greater than the estimated creatinine clearance (90 +/- 48 ml/min per 1.73 m2). After probenecid administration, there was a 32% decline in renal clearance (248 to 168 ml/min per 1.73 m2; P less than or equal to 0.05), a 40% increase in the area under the curve (91.3 to 127.6 nmol.h/ml; P less than 0.05), and an 18% increase in the terminal plasma half-life (2.3 to 2.7 h; P less than 0.01). Although statistically significant, these effects due to the influence of probenecid probably have only limited clinical importance. In this study we confirmed that acyclovir is eliminated predominantly by renal clearance, both by glomerular filtration and tubular secretion; our results suggested that at least part of the tubular secretion is inhibited by probenecid.