Oscar L. Laskin

Acyclovir prophylaxis of herpes-simplex-virus infections. A randomized, double-blind, controlled trial in bone-marrow-transplant recipients.

We conducted a double-blind, placebo-controlled study of acyclovir prophylaxis against infection with herpes simplex virus (HSV) in 20 seropositive recipients of bone-marrow transplants. Acyclovir or placebo was administered for 18 days, starting three days before transplantation. Culture-positive HSV lesions developed during the study in seven of the 10 patients who received placebo. In contrast, no such lesions appeared in the 10 patients who received acyclovir (P congruent to 0.003). None of the patients had evidence of drug toxicity. Five of the patients treated with acyclovir had mild culture-positive HSV infections after cessation of the drug, and two additional patients shed virus without having lesions. Acyclovir appears to be a potent inhibitor of HSV replication. Although acyclovir does no appear to eradicate latent infection, it can provide effective prophylaxis against reactivated infections.

Double-Blind Comparison of the Nephrotoxicity and Auditory Toxicity of Gentamicin and Tobramycin

Two hundred fifty-eight patients with suspected sepsis were treated with tobramycin or gentamicin in a prospective, randomized, double-blind trial. One hundred forty-six patients received nine or more doses, had serial determinations of serum creatinine, and were evaluated for nephrotoxicity; 91 were able to cooperate with audiometry and were evaluated for auditory toxicity. Auditory toxicity developed in five of 47 (10 per cent) given gentamicin and five of 44 (11 per cent) given tobramycin. Nephrotoxicity developed in 19 of 72 (26 per cent) given gentamicin and nine of 74 (12 per cent) given tobramycin (P less than 0.025). The severity of the nephrotoxicity was not different; the mean increase in creatinine was 1.3 mg per 100 ml (114.9 mumol per liter) in both groups. Both the tobramycin and gentamicin groups had a similar mean age, initial serum creatinine level, total dose, serum aminoglycoside level, and duration of therapy. We conclude that tobramycin causes nephrotoxicity less frequently than does gentamicin.

A Short-Term Clinical Evaluation of L-697,661, a Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase

Background The non-nucleoside reverse transcriptase inhibitors are novel antiretroviral agents with selective activity in vitro against human immunodeficiency virus type 1 (HIV-1). They act through direct inhibition of reverse transcriptase and are not incorporated into DNA. Methods We evaluated a pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661, in separate six-week double-blind trials in patients with HIV-1 infection whose CD4 counts ranged from 200 to 500 cells per cubic millimeter (68 patients) or less than 200 cells per cubic millimeter (67 patients). Eligible patients were randomly assigned to receive L-697,661 orally in one of three doses (25 mg twice a day, 100 mg three times a day, or 500 mg twice a day) or zidovudine (100 mg five times a day). Clinical and laboratory assessments were performed weekly. Viral isolates were obtained from a subgroup of patients before and after treatment and were evaluated for in vitro sensitivity to L-697,661. Results Both L-697,661 and zidovudi...

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.

Disposition of intravenous radioactive acyclovir

The kinetic and metabolic disposition of (8‐14C)acyclovir (ACV) was investigated in five subjects with advanced malignancy. The drug was administered by 1‐hr intravenous infusion at doses of 0.5 and 2.5 mg/kg. Plasma and blood radioactivity‐time, and plasma concentration‐time data were defined by a two‐compartment open kinetic model. There was nearly equivalent distribution of radioactivity in blood and plasma. The overall mean plasma half‐life and total body clearance ± SD of ACV were 2.1 ± 0.5 hr and 297 ± 53 ml/min/1.73 m2. Binding of ACV to plasma proteins was 15.4 ± 4.4%. Most of the radioactive dose excreted was recovered in the urine (71% to 99%) with <2% excretion in the feces and only trace amounts in the expired CO2. Analyses by reverse‐phase high‐performance liquid chromatography indicated that 9‐(carboxymethoxymethyl)guanine was the only significant urinary metabolite of ACV, accounting for 8.5% to 14.1% of the dose. A minor metabolite (<0.2% of dose) had the retention time of 8‐hydroxy‐9‐[(2‐hxdroxyethoxy)methyl]guanine. Unchanged urinary ACV ranged from 62% to 91% of the dose. There was no indication of ACV cleavage to guanine. Renal clearance of ACV was approximately three times the corresponding creatinine clearances.

Pharmacokinetics and tolerance of acyclovir, a new anti-herpesvirus agent, in humans.

The pharmacokinetics and tolerance of acyclovir administered intravenously in single doses of 2.5, 5.0, 10.0, and 15.0 mg/kg were studied in 13 volunteers. The mean concentrations (+/- standard deviations) at the end of infusion as measured by radioimmunoassay were 4.52 +/0 0.31, 8.28 +/- 2.61, 14.6 +/- 2.30, and 22.7 +/- 10.4 microgram/ml, respectively. Drug elimination during and after the infusion of acyclovir was well described by a two-compartment open model. The mean terminal plasma half-life for each of the groups was 2.85, 2.80, 3.30, and 2.38 h, respectively. Within 72 h after the start of the infusion, 70% of the administered drug was recovered in the urine as unchanged acyclovir. The renal clearance of acyclovir accounted for about 77% of the total clearance and was about threefold greater than the creatinine clearance. This confirms that acyclovir is eliminated predominantly by the kidneys in patients with normal renal function and suggests that renal secretion and glomerular filtration may both be involved. The only adverse effect found by clinical and laboratory monitoring was irritation at he intravenous site after extravasation (in two cases), which resolved without significant sequelae.

Effect of renal failure on the pharmacokinetics of acyclovir

Abstract To determine the effect of renal failure on the pharmacokinetics of acyclovir in patients with end-stage renal disease (ESRD), we studied six anuric subjects on chronic hemodialysis. Each subject received a single one-hour intravenous infusion of acyclovir (2.5 mg/kg). We compared these anuric subjects with 13 subjects with normal renal function (NRF) who had received a single dose of acyclovir (2.5 to 15 mg/kg) in an identical fashion. The kinetics were well-described by a two-compartment open model. The mean terminal plasma half-life of acyclovir in subjects with ESRD was 19.5 ± 5.9 hours (mean ± SD) compared with 2.9 ± 0.8 hours in our subjects with NRF. In subjects with renal failure the mean (± SD) peak, eight- and 24-hour plasma acyclovir concentrations were 37.5 ± 23.3, 10.3 ± 2.9, and 6.4 ± 2.4, μ M respectively. Forty-eight hours after the start of acyclovir infusion, the subjects were hemodialyzed for six hours. The pre- and post-hemodialysis acyclovir plasma levels were 2.74 ± 1.38 and 1.11 ± 0.60 μ M , respectively. The total body clearance of acyclovir (28.6 ± 9.5 ml/min/1.73 m 2 ) in ESRD was found to be approximately 10 percent of that previously seen in subjects with normal renal function (307 ± 98.4 mg/min/1.73 m 2 ). The volume of distribution at steady state was significantly less in the subjects with ESRD than in subjects with NRF. Acyclovir was readily hemodialyzable with an extraction coefficient of 0.45 ± 0.12 and a fourfold enhancement in the elimination of acyclovir during dialysis. Suggestions for acyclovir dosage modifications for patients with ESRD are provided.

Acyclovir kinetics in end‐stage renal disease

Acyclovir (ACV) is almost entirely eliminated by the kidneys and has a terminal plasma half‐life (t½) of 2 to 3 hr in subjects with normal renal function. To determine the drugs kinetics and tolerance in patients with severe renal failure, six anuric subjects on long‐term hemodialysis were studied. Each received a 1‐hr infusion of 2.5 mg/kg IV ACV. The kinetics are well described by a two‐compartment open model. ACV terminal plasma t½ and the total body clearance were 19.5 ± 5.9 hr (x̄ ± SD) and 28.6 ± 9.5 ml / min / 1.73 m2. Peak (end of infusion) and 8‐ and 24‐hr plasma ACV concentrations were 37.5 ± 23.3, 10.3 ± 2.9, and 6.4 ±2.4 μM. Approximately 48 hr after the start of the infusion the subjects were hemodialyzed for 6 hr. The pre‐ and posthemodialysis ACV plasma levels were 2.74 ± 1.38 and 1.11 ± 0.60 μM. The terminal ACV t½ during hemodialysis was 5.7 ± 0.85 hr. During hemodialysis paired arterial and venous samples showed that ACV was readily dialyzed, with a mean coefficient of extraction of 0.45 ± 0.12. The dialysis clearance of acyclovir was 81.8 ± 12.6 ml / min. None of the patients had any ACV‐related adverse effects. Since ACV elimination is markly reduced in end‐stage renal failure and because ACV is readily hemodialyzible, dosage modifications are needed to avoid cumulation and to replace dialyzed drug.

Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure

The pharmacokinetic disposition of acyclovir was studied in six patients with chronic renal failure (CRF) and anuria. At the end of a one-hour intravenous infusion (2.5 mg/kg), the mean peak acyclovir plasma level (+/- SD), determined by radioimmunoassay, was 37.5 +/- 24.2 microM (8.4 +/- 5.4 microgram/ml), twice the level found at this dose in patients with normal renal function (NRF). In the CRF volunteers, significant plasma levels (3.0 +/- 1.4 microM) persisted at 47 hours after drug administration (before hemodialysis) whereas in the NRF patients levels dropped to less than 1 microM by 11 hours. Hemodialysis was started 47 hours after infusion and was continued for six hours. The pre-dialysis plasma drug level was reduced by 61.5 percent at 0.25 to 1.5 hours after the end of dialysis. The mean plasma t 1/2 during dialysis of 5.4 hours, the extraction ratio of 0.44, and the dialysis clearance for plasma of 113 ml/min indicate that acyclovir is efficiently removed by hemodialysis. One-half the suggested intravenous dose for a particular indication can be given every 24 hours and a similar replacement dose should be given after each dialysis.

Metabolic fate of radioactive acyclovir in humans

The metabolic fate and the kinetics of elimination of [8-14C]acyclovir in plasma and blood was investigated in five cancer patients. Doses of 0.5 and 2.5 mg/kg were administered by one-hour intravenous infusion. Radioactivity was distributed nearly equally in blood and plasma. The plasma and blood concentration-time data were defined by a two-compartment open pharmacokinetic model. The overall mean acyclovir plasma half-life and total body clearance +/- SD were 2.1 +/- 0.5 hours and 297 +/- 53 ml/min/1.73 m2. Binding of acyclovir to plasma proteins was 15.4 +/- 4.4 percent. The radioactive dose was excreted predominantly in the urine (71 to 99 percent) with less than 2 percent excretion in the feces and only trace amounts of radioactivity in the expired air. Reverse-phase high-performance liquid chromatography indicated that 9-carboxymethoxymethylguanine was the only significant urinary metabolite of acyclovir accounting for 8.5 to 14.1 percent of the dose. A minor metabolite (less than 0.2 percent of dose) had the retention time of 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. Unchanged urinary acyclovir ranged from 62 to 91 percent of the dose. There was no indication of acyclovir cleavage to guanine. The renal clearances of acyclovir were three times higher than the corresponding creatinine clearances.