Acyclovir. Pharmacology and clinical experience.

Acyclovir is a selective antiherpes agent. Its selective activity is by exploitation of differences between the herpes-specific and host cell enzymes. The major route of elimination of acyclovir is via the kidney by glomerular filtration and renal tubular secretion. In immunocompromised patients, acyclovir is effective for the prophylaxis and therapy of herpes simplex virus infections and for the treatment of herpes zoster and varicella. In nonimmunocompromised patients, acyclovir is beneficial in the therapy of herpes keratoconjunctivitis and in the therapy of genital herpes, with maximal benefit seen in those patients who have primary genital herpes. There is some benefit from acyclovir administration in patients with herpes zoster who are otherwise normal. The toxic reactions to acyclovir consist of phlebitis, local irritation, and occasionally, reversible renal dysfunction. Dose reduction is recommended in patients with impaired renal function.

Pentamidine-induced hypoglycemia in patients with the acquired immune deficiency syndrome.

We conducted an analysis of 37 patients with the acquired immune deficiency syndrome (AIDS) who received pentamidine for the treatment of Pneumocystis carinii pneumonia to quantitate the incidence and severity of pentamidine-induced hypoglycemia. Ten of these patients (27%), nine of whom were symptomatic, developed hypoglycemia during or shortly after pentamidine therapy. The mean nadir blood glucose concentration in those who developed hypoglycemia during or shortly after pentamidine therapy was 38 mg/dl (range 20 to 55 mg/dl). The hypoglycemia frequently persisted after the end of pentamidine therapy. The incidence of nephrotoxicity in patients who developed hypoglycemia was 100%, as compared with 38% in the group who remained euglycemic (P less than 0.01). The overall incidence of pentamidine-induced hypoglycemia with AIDS is several-fold higher than previously reported for patients with other immunocompromising diseases who receive pentamidine. We conclude that pentamidine-induced hypoglycemia is a frequent adverse reaction in patients with AIDS and is potentially life-threatening if not recognized.

Pharmacodynamics and tolerability of L-654,066, a steroid 5 alpha-reductase inhibitor, in men.

A four-period, two-panel single rising-dose study (0.1 to 100 mg) was conducted in healthy men to investigate the pharmacodynamics and tolerability of L-654,066, a steroid 5 alpha-reductase inhibitor. Within each panel, six subjects received L-654,066 and two subjects received placebo at each dose level; the placebo subjects changed between periods so that each subject received placebo once. Testosterone and dihydrotestosterone were measured in serum at 0, 4, 24, and 48 hours after each treatment. L-654,066 was associated with a significant reduction in serum dihydrotestosterone concentrations, which was maximal at 48 hours after dose. Forty-eight hours after treatment, mean percentage of inhibition was 24% and 39% for the 0.1 and 0.5 mg doses, respectively, and ranged from 50% to 65% at doses from 1 to 25 mg and from 70% to 75% at doses from 50 to 100 mg. Testosterone serum levels did not show any significant difference between the various treatments, including placebo.

Netilmicin and gentamicin multidose kinetics in normal subjects.

Multidose netilmicin and gentamicin kinetics were studied in 20 healthy subjects who received 1.7 mg/kg gentamicin (n = 10) or netilmicin (n = 10) as a 20-min infusion every 8 hr for 10 days (28 doses) during a randomized, double-blind comparative trial designed to study adverse effects and kinetics of netilmicin and gentamicin. Multidose kinetics were of the same order for gentamicin and netilmicin with the exception of the terminal plasma t 1/2 (94 and 156 hr) and the volume of distribution at steady state (450 and 1072 ml/kg). Mean peak plasma concentrations of netilmicin were slightly lower than gentamicin. Percentage of the dose eliminated in urine did not differ for the two aminoglycosides. Aminoglycoside was detectable in plasma and continued to be eliminated in urine for at least 6 days after the final dose. The plasma concentration-time profiles for both netilmicin and gentamicin were well fitted with the sum of three exponential terms; urinary excretion rates-time plots showed biexponential decay. None of the subjects had any auditory, vestibular, or renal toxicity. Although the data confirm a deep tissue compartment, they suggest that the kinetic processes involved may be more complex than previously supposed.

Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome.

Ribavirin is a broad-spectrum antiviral drug that has in vitro activity against human immunodeficiency virus. To determine the kinetics of ribavirin, 17 symptom-free homosexual men with lymphadenopathy were studied. Single doses of ribavirin, 600, 1200, or 2400 mg, were given orally or intravenously. The plasma ribavirin concentration-time profiles were well fitted by a three-compartment open model. Ribavirin followed linear kinetics over the dose range studied. The mean 1-hour postinfusion concentrations after intravenous ribavirin, 600, 1200, and 2400 mg, were 8.0, 19.7, and 37.1 mumol/L, respectively. The mean +/- SD plasma beta-phase half-life, terminal-phase (gamma) half-life, and volume of distribution at steady state were 2.0 +/- 1.1 hours, 35.5 +/- 14.0 hours, and 647 +/- 258 L, respectively. The mean ribavirin renal clearance and total body clearance were 99 +/- 30 and 283 +/- 37 ml/min, respectively. After an oral dose of 600, 1200, and 2400 mg, the mean peak plasma ribavirin concentrations (which occurred 1.5 hours after administration) were 5.1, 9.9, and 12.6 mumol/L, respectively. The mean absorption half-life and bioavailability of ribavirin were 0.5 hour and 45%. Ribavirin had no plasma protein binding and the drug accumulated within red blood cells. In conclusion, ribavirin is incompletely absorbed from the gastrointestinal tract, its renal excretion accounts for approximately one third of the drug's elimination, and drug accumulation (greater than threefold) will result with repetitive dosing at the 6- to 8-hour dosing interval currently used.

Ribavirin pharmacodynamics in high-risk patients for acquired immunodeficiency syndrome.

Ribavirin was administered orally in escalating doses for 2 or 4 weeks to 15 symptom-free, human immunodeficiency virus seropositive homosexual men with generalized lymphadenopathy. Reverse transcriptase activity was inhibited during therapy when steady-state plasma concentrations were greater than 6 mumol/L. These concentrations were achieved with 1200 or 2400 mg/day for 2 weeks or a loading dose of 2400 mg/day for 3 days followed by 600 mg/day for 4 weeks. Drug accumulation occurred at all doses. The elimination half-life appeared to be approximately 2 weeks. Reversible adverse reactions, principally resulting in central nervous system symptoms and anemia, correlated with dose and duration of therapy. Immunologic enhancement of T-lymphocyte-mediated mitogen-induced responses was observed in the majority of patients who had reduction in reverse transcriptase activity. However, specific T4+ lymphocyte-mediated antigen-induced responses increased to within the normal range in only three patients. Significant enhancement appeared to correlate with the severity of baseline antigen-induced functional impairment. These data indicate that oral ribavirin can be given for at least 1 month with acceptable toxicity at doses that appear to inhibit human immunodeficiency virus replication.

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 less than 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 (less than 0.2% of dose) had the retention time of 8-hydroxy-9-[(2-hydroxyethoxy)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.

Acyclovir kinetics in end-stage renal disease.

Acyclovir (ACV) is almost entirely eliminated by the kidneys and has a terminal plasma half-life (t1/2) of 2 to 3 hr in subjects with normal renal function. To determine the drug's 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 t 1/2 and the total body clearance were 19.5 +/- 5.9 hr (mean +/- 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 microM. 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 microM. The terminal ACV t1/2 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 markedly reduced in end-stage renal failure and because ACV is readily hemodialyzible, dosage modification are needed to avoid cumulation and to replace dialyzed drug.

Pharmacodynamics of MK-0963, a new 5 alpha-reductase inhibitor: effects on serum androgen concentrations.

The hormonal effects after a 10-day administration of a 4-azasteroid inhibitor of 5 alpha-reductase, MK-0963 (previously L-654,066), were evaluated in 35 healthy male volunteers in an increasing-dose, five-panel design. Marked suppression of serum dihydrotestosterone was observed after the once-daily administration at each active dose level (placebo, 0.1, 0.5, 1.0, 10, and 25 mg). Maximum dihydrotestosterone suppression occurred at doses greater than or equal to 10 mg. The mean percentage (+/- SE) decreases in dihydrotestosterone at 24 hours after the last dose in the groups treated with the 10 and 25 mg doses were 78% +/- 4.9% and 80% +/- 2.9%, respectively. The 25 mg dose maintained a dihydrotestosterone suppression of at least 70% for more than 6 days after the last dose. No consistent changes in serum testosterone were noted. This study shows that administration of multiple doses of MK-0963 results in a substantial suppression of serum dihydrotestosterone with no consistent influence on serum testosterone concentrations.

Concomitant herpes simplex virus type 1 and cytomegalovirus ventriculoencephalitis in acquired immunodeficiency syndrome.

Three patients with the acquired immunodeficiency syndrome (AIDS) had combined infections of the central nervous system, with both herpes simplex virus (HSV) and cytomegalovirus (CMV). All three had a diffuse ventriculoencephalitis documented at postmortem examination. The presence of HSV type 1 and CMV was confirmed microscopically with immunohistochemistry. The clinical importance of these three patients is that they establish the presence of concomitant HSV and CMV encephalitis in acquired immunodeficiency syndrome, and suggests the possibility of therapeutic intervention with antiviral drugs that have activity against HSV and/or CMV.

Herpes zoster and zosteriform herpes simplex virus infections in immunocompetent adults.

Among 111 immunocompetent patients referred to a general hospital setting with the clinical diagnosis of herpes zoster, viral cultures were obtained from 47 patients. Six of these patients (13 percent) had herpes simplex virus isolated, with four of the six infections involving the facial distribution, and the other two involving the T4 (breast) distribution. Excluding those in whom herpes simplex virus was isolated, the mean age (+/- SD) of the remaining 105 patients was 50 +/- 19 years. Thirty-two percent of the patients were at least 65 years old; however, 39 percent were younger than 40 years of age. Thus, herpes zoster frequently occurs in young, immunocompetent adults. Also, since zosteriform rashes may be caused by herpes simplex virus, viral cultures of lesions are useful to differentiate infections caused by herpes simplex virus from those due to varicella-zoster virus. The need to distinguish between these two viruses may be important with the advent of antiviral drugs and for use of the proper epidemiologic isolation procedures.

Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus.

Ganciclovir is a congener of acyclovir with in vitro activity against cytomegalovirus. Ninety-seven patients with the acquired immune deficiency syndrome (AIDS) and a serious cytomegalovirus infection received ganciclovir, 3.0 to 15 mg/kg per day. Viremia cleared during drug therapy in 88 percent of patients. Viral shedding from urine and throat ceased or became inapparent during treatment in 78 percent and 68 percent of patients, respectively. Among patients with cytomegalovirus retinitis, 87 percent of evaluable patients had improvement in (30 of 60) or stabilization (22 of 60) of their disease. However, when the drug was discontinued, progression or recurrence of disease always occurred. Long-term suppressive therapy with ganciclovir, 5.0 mg/kg five to seven times weekly, prevented the recurrence of cytomegalovirus disease (p less than 0.001). The drug was eliminated by renal excretion, and in patients without renal impairment (creatinine clearance rates of more than 60 ml/minute/1.73 m2), ganciclovir has a mean half-life of 4.2 hours. Significant neutropenia and leukopenia occurred in 55 percent and 32 percent of patients, respectively.

Acyclovir concentrations and tolerance during repetitive administration for 18 days.

Acyclovir, a new antiherpetic agent, was administered for 18 days to 10 recipients of bone marrow transplants as a part of a double-blind, randomized, placebo-controlled trial assessing its prophylactic efficacy and safety. Renal glomerular function diminished over the time of the study in the 10 acyclovir-treated and 10 placebo-treated patients. The decline in glomerular filtration rate (GFR) did not differ significantly between the two groups and is unlikely to be associated with acyclovir. The pharmacokinetics of acyclovir is expected to be altered by a change in GFR since glomerular filtration is probably the major process involved with the excretion of acyclovir. Such an alteration was seen as an increase over time of both peak (one hour after the end of an infusion) and trough (immediately before a dose) plasma acyclovir concentrations. Although peak and trough acyclovir concentrations rose from 8.5 to 15.8 microM and from 1.7 to 4.1 microM, respectively, these rises are fully attributable to the decreases in GFR seen in both drug- and placebo-treated groups. The placebo-controlled and blinded nature of this trial allows an assessment of the effects of acyclovir on a battery of hematologic, renal, and hepatic tests. The only adverse effects observed that statistically differed in the acyclovir-treated group compared with controls were the rises in SGOT (53.2 +/- (SEM) 19.9 versus 3.1 +/- 12.2) and SGPT (59.7 +/- 15.3 versus 12.3 +/- 13.8).

Therapy of herpes zoster with oral acyclovir.

Oral acyclovir therapy for herpes zoster has been studied in double-blind, placebo-controlled trials of two dosages, 400 mg and 800 mg five times per day for 10 days. Compared with placebo recipients, recipients of the high-dosage acyclovir experienced a significantly shortened period of viral shedding, significantly accelerated time to 50 percent scabbing, significantly accelerated time to 50 percent healing, and after two days of therapy, significantly less frequent formation of new lesions. The duration and severity of acute pain were less in acyclovir recipients, with differences in pain severity achieving statistical significance (p = 0.03) between Days 3 and 10 and correlating with the treatment differences in new lesion formation. In studies of the 400 mg five times per day dose schedule, differences between acyclovir and placebo recipients were not significant. In a six-month follow-up of recipients in the higher dosage study, the acyclovir recipients experienced less post-zoster pain than placebo recipients; differences in the prevalence of pain were most significant for the presence of a persistent pain in the first three months of follow-up. Oral acyclovir at these dosages appears to be free of adverse reactions. In summary, oral acyclovir at a dosage of 800 mg five times per day for 10 days for treatment of acute herpes zoster is superior to 400 mg five times per day and favorably alters the course of the disease.

Prospective randomized double-blind comparison of moxalactam and tobramycin in treatment of urinary tract infections.

In a prospective, randomized, double-blind trial, a regimen of 250 mg of moxalactam every 12 hours was compared with 1.0 mg/kg of tobramycin every eight hours in the treatment of urinary tract infections. One hundred and eleven patients were entered into the study; results in 63 (18 men and 45 women) were evaluable for both efficacy and toxicity. Thirty evaluable patients received moxalactam, and 33 received tobramycin. The mean duration of therapy in each group was seven days. There were six treatment failures in the moxalactam group and 10 failures in the tobramycin group (p greater than 0.4). Nephrotoxicity, defined as an increase in serum creatinine levels to 0.5 mg/dl or more, did not occur in either group. Thirteen patients in the moxalactam group and one in the tobramycin group had enterococci isolated from a urine culture specimen during or after therapy. It is concluded that use of the moxalactam regimen is as effective and safe as use of the tobramycin regimen in the treatment of urinary tract infections. The clinical significance of the enterococcal isolates associated with moxalactam therapy is yet to be determined.

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.

Changes in cerebrospinal fluid cells, IgG and IgA during herpes simplex virus encephalitis in rabbits.

Rabbits were infected with herpes simplex-type 1 virus either by corneal scarification or intrathecal inoculation. Encephalitis was induced predictably by either route but was most severe after intrathecal inoculation. Serial examination of the cerebrospinal fluid (CSF) demonstrated abnormalities reflecting two distinct phases of the immune response to this central nervous system infection. The acute phase was manifested by a mononuclear pleocytosis and transudation of serum proteins into the CSF. The recovery phase was manifested by increased amounts of IgG, IgA and antibody specific for herpes simplex virus in the CSF. These studies demonstrate that IgA is a significant component of the local immune response to viral encephalitis in the rabbit as well as in mice and man.

Pharmacodynamics and dose-response relationship of famotidine: a double-blind randomized placebo-controlled trial.

The dose-response relationship of oral famotidine at doses up to 10 mg was evaluated in 10 healthy male subjects to assess the extent and duration of inhibition of meal-stimulated intragastric acid secretion. Each subject received single oral administrations of famotidine 0.5, 2.5, 5.0, and 10.0 mg and placebo in a double-blind, randomized, cross-over fashion. Intragastric pH was measured every 4 seconds for 24 hours and expressed as the mean pH for each 10-minute interval. Standard high-protein meals were provided 1 hour before each dose of study drug and at 3 and 9 hours postdose. The mean intragastric pH was significantly higher after famotidine doses 2.5, 5.0, and 10.0 mg than after placebo at times 2.5 to 3.0, 1.8 to 3.2, and 1.7 to 4.2 hours postdose, respectively. There were no significant differences in mean pH seen between famotidine 0.5 mg versus placebo. The range of the pH means between 1.7 and 3.2 hours postdose was placebo (1.0 to 1.3), famotidine 0.5 mg (1.1 to 1.4), 2.5 mg (1.4 to 1.7), 5.0 mg (1.7 to 2.1), and 10.0 mg (2.0 to 2.3). There was a statistically significant linear dose-response relationship between famotidine dose and intragastric pH between 1.7 and 3.8 hours and from 6.3 to 8.7 hours after ingestion.

Antiviral therapy for cytomegalovirus retinitis in AIDS with dihydroxy propoxymethyl guanine.

Six patients (all male, five homosexual and one bisexual, 23 to 48 years old) with the acquired immune deficiency syndrome (AIDS) who had cytomegalovirus retinitis were treated with a new antiviral drug as a part of a prospective open-labeled trial for serious cytomegalovirus infections. The drug, 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl] guanine (referred to as dihydroxy propoxymethyl guanine), a new acyclic nucleoside antiviral agent similar in structure to acyclovir, produced positive results. These patients treated with dihydroxy propoxymethyl guanine (2.5 mg/kg of body weight every eight hours) showed regression and often disappearance of the lesions of cytomegalovirus retinitis during and for several weeks after therapy, usually with concomitant resolution of viral shedding. The cytomegalovirus retinitis recurred in four patients (the other two were lost to follow-up), but retreatment usually led to remission. Adverse drug toxicity (reversible granulocytopenia) occurred in two patients.