Famciclovir, a new antiviral agent, was approved for marketing by the Food and Drug Administration in June 1994 for the management of acute herpes zoster. Famciclovir is the well-absorbed (77% bioavailable) [11] oral form of penciclovir, with activity against varicella-zoster virus, herpes simplex virus types 1 and 2, and Epstein-Barr virus [12-15]. Penciclovir is selectively activated in virus-infected cells through phosphorylation to the antiviral compound penciclovir triphosphate. Viral thymidine kinase converts penciclovir to penciclovir monophosphate, which is converted by cellular enzymes to penciclovir triphosphate [12, 16, 17]. Penciclovir triphosphate inhibits viral DNA polymerase, thereby halting DNA synthesis and viral replication [16-19].

The in vitro potencies of penciclovir and acyclovir depend on the tissue culture cell line and assay method used but are generally similar [14, 15, 20].^The 50% plaque inhibitory concentrations in human lung fibroblasts infected with varicella-zoster virus were 4.0 ±1.5 µg/mL for penciclovir and 4.0 ±1.1 µg/mL for acyclovir [14]. A potentially clinically important characteristic of penciclovir triphosphate is that it persists in virus-infected host cells longer than acyclovir triphosphate [19]. For cells infected with varicella-zoster virus, the intracellular half-life of penciclovir triphosphate is 9.1 hours; in contrast, the half-life for acyclovir triphosphate is 0.8 hours [19, 21]. Thus, penciclovir triphosphate has the potential to continue to inhibit viral replication even if serum concentrations are below the inhibitory level.

Consistent oral bioavailability linked to a favorable intracellular half-life of penciclovir triphosphate in cells infected with varicella-zoster virus suggested that famciclovir could offer clinically important advantages in the management of herpes zoster over currently available therapy. These advantages include a reduced total daily dose and a reduced dosing frequency. Because persistent antiviral activity throughout each day of dosing was expected to lead to improved clinical efficacy, especially with regard to postherpetic neuralgia, we examined the effects of famciclovir on acute herpes zoster and postherpetic neuralgia.

Methods

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Study Design

In our randomized, double-blind, placebo-controlled, multicenter trial, we compared the efficacy and safety of famciclovir, 500 mg or 750 mg, given three times daily for 7 days, with that of placebo in the treatment of patients with uncomplicated acute herpes zoster.

Eligible participants were immunocompetent patients 18 years or older with clinically diagnosed uncomplicated herpes zoster who gave written informed consent. Exclusion criteria included zoster rash that had been present for more than 72 hours; complications of herpes zoster (for example, ocular or visceral involvement, disseminated herpes zoster); presence of crusts at enrollment; other serious underlying disease (such as immune disorders or human immunodeficiency virus [HIV] infection); or pregnancy or lactation.

Patients were prohibited from receiving any concomitant antiviral or immunomodifying therapy and any topical medication that would be applied to zoster lesions during the study.

Patient Assessments

Patients were instructed to return to the clinic for evaluation of lesions and pain on each of the 7 therapy days and every day for the 7 days after therapy. Patients with lesions that were fully crusted by day 7 were examined every other day during the week after therapy. After day 14, weekly visits were required of all patients until all lesions had lost their crusts. After the lesions had healed, patients were assessed for the presence of postherpetic neuralgia (defined as pain after healing) at monthly intervals for an additional 5 months. These monthly pain assessments continued for all patients, even if postherpetic neuralgia had resolved before completion of the study period. Patients attending the clinic for fewer than 80% of required visits were deemed noncompliant.

The number of papules, vesicles, ulcers, and crusts within the primary dermatome was classified as none, mild (<25 lesions), moderate (25 to 50 lesions), or severe (>50 lesions). A specimen for viral culture was obtained at baseline and daily thereafter while vesicles were present. Patients were asked to rate the intensity of their pain as none, mild, moderate, or severe. Definitions for mild, moderate, and severe pain were not prospectively provided.

Adverse events were assessed at each visit according to the time of onset, duration, severity, and investigator-defined relation to the study medication. Blood samples were obtained for chemical and hematologic assessment, and urine samples were obtained for dipstick analysis before initiation of therapy and at the last therapy visit.

Statistical Analysis

Efficacy end points were analyzed by standard survival methods. We used the Cox proportional-hazards regression model in our analyses [22]. Time-dependent covariates were modeled to evaluate the proportional hazards assumption, and a model that included the main effects of treatment was used to examine efficacy. Statistical conclusions were based on the significance of estimated hazard ratios. Hazard ratios greater than 1 indicated a faster rate of event occurrence in patients receiving famciclovir than in those receiving placebo. An estimated hazard ratio of 2 indicated that the event of interest occurred twice as rapidly in patients receiving famciclovir as it did in placebo recipients. Two comparisons were made for each end point: 500-mg famciclovir compared with placebo and 750-mg famciclovir compared with placebo. We also used Kaplan-Meier estimates of the cumulative proportion of patients achieving an event to graphically illustrate the trial results. We used the Fisher exact test (two-tailed) to analyze proportion data.

The primary efficacy variable was the time to full crusting of the lesions. Secondary variables included duration of viral shedding; time to resolution of vesicles, ulcers, crusts, and acute pain; and duration of postherpetic neuralgia (that is, the time to resolution of pain after the lesions had healed). Healing was defined as the first time in which a patient had no papules, vesicles, ulcers, or crusts and after which did not develop them at any later visit. Similarly, the time to the resolution of a clinical variable was the time to the complete cessation of that variable with no further occurrence at any later date. Duration of viral shedding was measured as the number of days from the first dose of the study medication to the last positive culture.

The enrollment objective before the study was 400 patients; this number was selected to ensure a target of 300 evaluable patients (100 per group). The sample provided an 80% power to detect a significant difference from placebo, assuming a true hazard ratio of 1.5 and exponential time to full crusting (or time to event). We analyzed data from both the intention-to-treat group (patients receiving at least one dose of study medication) and the efficacy-evaluable group (patients complying with the protocol). We prospectively defined the efficacy-evaluable group before unblinding the randomization code.

Because the results of both analyses were generally similar, we present data for the intention-to-treat group, unless otherwise specified. We also examined prospectively defined subgroups with respect to age, duration of rash at enrollment, and severity of rash at enrollment. The safety analysis included all patients who had received at least one dose of the study medication. Each analysis included all patients who provided information for the respective end point. For example, the analysis for the time to resolution of crusts included all patients who presented with crusts during the study. Therefore, the number of patients in each analysis of the time to resolution of a condition may vary because only patients experiencing the specific condition were included in the analysis.

Results

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Demographic Characteristics

Characteristics of patients in the intention-to-treat group (n = 419), including sex, age, duration of rash, location of rash, severity of rash, and severity of pain, are shown in Table 1. Of the 419 patients enrolled, 138 received 500 mg of famciclovir, 135 received 750 mg of famciclovir, and 146 received placebo. Approximately half of the patients were female, and the mean age was 50 years. More than half of the patients had severe rash (>50 lesions) at enrollment, and more than 60% had moderate or severe zoster pain at enrollment.

The intention-to-treat group and the efficacy-evaluable group (n = 323) had similar baseline characteristics. The distribution of patients excluded from the efficacy-evaluable analyses and the reasons for exclusion were similar across the three treatment groups. The most common reasons for exclusion from the efficacy-evaluable analyses were crusts at entry, a compliance with study medication of less than 80%, HIV seropositivity, and positive cultures for herpes simplex virus (Table 2).

Compliance

During the acute phase of illness, five patients did not comply with the required visits (Table 2). In the postherpetic neuralgia phase of the illness, almost 90% of patients were assessed for 5 months after the lesions had healed.

Dermatologic Assessment

Famciclovir treatment accelerated lesion healing compared with placebo, as shown by shorter times to full crusting and resolution of vesicles, ulcers, and crusts. In general, results of the analyses for the intention-to-treat and the efficacy-evaluable groups were similar (Table 3).

In the intention-to-treat and efficacy-evaluable analyses, the hazard ratios indicate a 1.3- to 1.5-fold faster time to full crusting for both the 500-mg famciclovir group (hazard ratios in the intention-to-treat and efficacy-evaluable groups, 1.3 and 1.5, respectively) and the 750-mg famciclovir group (hazard ratios in the intention-to-treat and efficacy-evaluable groups, 1.4 and 1.5, respectively). However, statistically significant differences were detected for the recipients of 500 mg of famciclovir only in the efficacy-evaluable analysis (P = 0.02); for recipients of 750 mg of famciclovir, both the intention-to-treat and efficacy-evaluable analyses achieved statistical significance (P = 0.02).

Virologic Assessment

Viral cultures were obtained for 406 patients. Hazard ratios for the time to the last positive culture were 2.0 (95% CI, 1.4 to 3.0) for the 500-mg famciclovir group and 2.3 (CI, 1.5 to 3.3) for the 750-mg famciclovir group. This indicates that famciclovir recipients stopped shedding the virus approximately two times faster than placebo recipients. The reduction in the duration of viral shedding was statistically significant for both famciclovir groups (P = 0.0005 and P < 0.0001, respectively). At baseline, 55%, 66%, and 61% of patients in the 500-mg famciclovir, 750-mg famciclovir, and placebo groups, respectively, had positive cultures for varicella-zoster virus. Of the patients who had a positive culture at baseline, 53% of those receiving 500 mg of famciclovir and 59% of those receiving 750 mg of famciclovir had their last positive culture 1 day after initiation of treatment compared with 31% of those receiving placebo. The median time to the last positive culture was 1 day for both famciclovir groups (80 and 91 patients, respectively) and 2 days for placebo recipients (102 patients).

Assessment of Acute Pain

The median times to resolution of acute-phase pain were 20, 21, and 22 days for the 500-mg famciclovir (n = 132), 750-mg famciclovir (n = 133), and placebo (n = 142) groups, respectively. Hazard ratios were 1.2 (CI, 0.9 to 1.6) for the 500-mg famciclovir group and 1.1 (CI, 0.8 to 1.5) for the 750-mg famciclovir group. Statistically significant differences were only detected in the efficacy-evaluable analyses for the time to resolution of acute pain for 103 patients receiving 500 mg of famciclovir compared with 108 patients receiving placebo (hazard ratio, 1.5 [CI, 1.1 to 2.2]; P = 0.02; n = 103).

In addition, pain resolved faster in patients with severe rash (>50 lesions) at enrollment in both the 500-mg famciclovir group (hazard ratios for the intention-to-treat and efficacy-evaluable groups, 1.9 [CI, 1.3 to 3.0]; P = 0.0028; n = 77 and 2.9 [CI, 1.7 to 5.0]; P = 0.0001; n = 57) and the 750-mg famciclovir group (hazard ratios for the intention-to-treat and efficacy-evaluable groups, 1.3 [CI, 0.8 to 2.1]; P = 0.21; n = 71 and 2.0 [CI, 1.2 to 3.4]; P = 0.01; n =57) than in patients in the placebo group with severe rash (75 patients in the intention-to-treat group and 61 in the efficacy-evaluable group). In the intention-to-treat groups, the median times to the resolution of pain were 20 days for patients receiving 500 mg of famciclovir, 27 days for patients receiving 750 mg of famciclovir, and 30 days for patients receiving placebo. In the efficacy-evaluable groups, the median times were 20, 27, and 53 days, respectively. No consistent trends were noted for patients presenting with mild or moderate rash at enrollment.

Assessment of Postherpetic Neuralgia

Of the 419 study patients, 186 [44%] developed postherpetic neuralgia. The proportion of patients who had postherpetic neuralgia was similar in each of the three treatment groups. Both famciclovir doses achieved a statistically significant reduction in the duration of postherpetic neuralgia in all study patients Figure 1, top). Hazard ratios were 1.7 for the 500-mg famciclovir group and 1.9 for the 750-mg famciclovir group. This indicates an almost twofold reduction in the time to resolution of postherpetic neuralgia compared with placebo; the corresponding P values for both doses of famciclovir were 0.02 and 0.005, respectively (Table 4). The median times to resolution of postherpetic neuralgia were 63 days for the 500-mg famciclovir group, 61 days for the 750-mg famciclovir group, and 119 days for the placebo group.

View larger version (23K): [in this window] [in a new window]   Figure 1. Time to the resolution of postherpetic neuralgia (intention-to-treat analyses). Top. Time to the resolution of postherpetic neuralgia (PHN) for all patients by treatment group, 500-mg famciclovir compared with placebo (P = 0.02) and 750-mg famciclovir compared with placebo (P = 0.005). Bottom. Time to the resolution of postherpetic neuralgia for patients 50 years of age or older by treatment group, 500-mg famciclovir compared with placebo (P = 0.0044) and 750-mg famciclovir compared with placebo (P = 0.0030). The numbers at the bottom of each part are the numbers of patients assessed for pain at each monthly visit after lesions had healed.

In the subgroup of patients most likely to develop postherpetic neuralgia, that is, those 50 years of age or older, postherpetic neuralgia resolved 2.6 times faster in famciclovir recipients than in placebo recipients (P = 0.004 for the 500-mg famciclovir group and P = 0.003 for the 750-mg famciclovir group; Figure 1, bottom). The median times to the resolution of postherpetic neuralgia in these older patients were 63 days for the 500-mg famciclovir group, 63 days for the 750-mg famciclovir group, and 163 days for the placebo group. This represents a reduction of almost 3.5 months for famciclovir recipients. No benefit was seen for patients younger than 50 years.

Analyses Adjusting for Covariates

We examined the effect of covariates on the analyses of the time to full crusting and the time to the resolution of postherpetic neuralgia. The results of the stepwise regression model, in which only the important covariates were fitted (P < 0.2), are shown in Table 5. After we controlled for age group and duration and severity of rash at enrollment, the hazard ratios for the time to full crusting were 1.3 for the 500-mg famciclovir group and 1.4 for the 750-mg famciclovir group. These findings are in agreement with the results of the data analysis shown in Table 3. After we controlled for age group and severity of rash and pain at enrollment, the hazard ratios for the time to resolution of postherpetic neuralgia (2.0 for both famciclovir groups) are also similar to the hazard ratios for the unadjusted analysis (Table 4). Therefore, the treatment effect of famciclovir was maintained even when we controlled for important covariates.

Safety

Famciclovir was well tolerated, with a safety profile similar to that of placebo. The adverse events reported most frequently were headache (23.2% of patients receiving 500 mg of famciclovir, 22.2% of patients receiving 750 mg of famciclovir, and 17.8% of patients receiving placebo, respectively) and nausea (12.3%, 12.6%, and 11.6% of patients, respectively). For events indicated by the investigator as being related to study medication (classified as related, possibly related, unknown, or cases in which assessment was missing), the most common adverse events in the 500-mg famciclovir, 750-mg famciclovir, and placebo groups were headache (8.0%, 8.1%, and 6.8% of patients, respectively) and nausea (5.1%, 3.0%, and 8.2% of patients, respectively). Famciclovir was not associated with abnormal hematologic findings, liver function, clinical chemical findings, or urinalysis variables.

Discussion

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Famciclovir given three times daily for 7 days accelerated the rate of lesion resolution and achieved a statistically significant reduction in the duration of viral shedding. Most striking, however, was the statistically significant reduction in the duration of postherpetic neuralgia for patients who received famciclovir compared with those who received placebo. Famciclovir was well tolerated, with an incidence of adverse events similar to that of placebo. In an overall review of the data, we found no dose-response relation in efficacy or safety between the two famciclovir doses. Famciclovir, 500 mg, administered three times daily for 7 days was cleared for marketing by the Food and Drug Administration for the management of acute herpes zoster, largely on the basis of results from our placebo-controlled clinical trial, a similarly designed acyclovir-controlled trial [24], and the overall safety profile of famciclovir [25].

For many years, acyclovir given at a dosage of 800 mg five times daily for 7 to 10 days has been the only oral antiviral agent approved for the treatment of acute herpes zoster. Its effectiveness in lessening the acute signs and symptoms of herpes zoster has been established [6, 7, 26-28], but "the effects of acyclovir on postherpetic neuralgia are less clear cut" [10].

Postherpetic neuralgia is a common severe complication of herpes zoster. In the largest acyclovir zoster trial, McKendrick and colleagues [8] found no difference between acyclovir and placebo in either the incidence or the duration of postherpetic neuralgia, even though only those patients most at risk for development of postherpetic neuralgia were enrolled (that is, the elderly). In two smaller trials (Huff and colleagues [7] and Morton and Thompson [29]), in which young and elderly patients were enrolled in about equal proportions, data were presented on frequency and prevalence of postherpetic neuralgia, but neither paper commented on the duration of postherpetic neuralgia. Huff and colleagues [7] noted a significant difference in the frequency of postherpetic neuralgia between acyclovir and placebo recipients for months 1 to 3 but did not find differences in the frequency of pain during months 4 to 6. Morton and Thompson [29] reported that the monthly prevalence of chronic pain in the second and third months was significantly reduced for acyclovir recipients, but they did not observe a significant reduction for months 4 to 6. In a reanalysis [9] of the data from one of these studies, a significant effect was seen on all zoster-associated pain (that is, a continuum of pain from enrollment in the study until the symptoms had completely resolved), but postherpetic neuralgia was not addressed. Additionally, a recent study evaluated acyclovir administered for 7 or 21 days with or without concomitant prednisolone for the treatment of acute herpes zoster [10]. Because this study did not include a placebo control, no conclusion can be drawn about the effect of acyclovir on postherpetic neuralgia.

Postherpetic neuralgia has been defined in relation to acute zoster onset [6-8, 29], at time points ranging from 1 to 6 months after zoster rash appears, and, as was done in our study, in relation to the healing of zoster lesions [30, 31]. Because the definition of postherpetic neuralgia varies among studies, the comparability of patient groups may be shown by examining the prevalence of pain in the placebo recipients that persisted for 6 months after the onset of zoster rash. In our study, 18.5% of the placebo recipients reported pain 6 months after the rash developed; this value is in agreement with the prevalence of pain reported by placebo recipients in other studies [6, 8, 29].

In our study, both doses of famciclovir clearly produced a statistically significant reduction in the duration of postherpetic neuralgia compared with placebo. Of note is that we prospectively defined postherpetic neuralgia and used rigorous statistical methods to express the relative duration of postherpetic neuralgia between treatment groups over the entire follow-up (5 months after healing) as a single summary statistic (hazard ratio). In our study, the resolution of postherpetic neuralgia was identified as the time at which the patients reported no zoster-related pain and, most importantly, after which they never reported pain again for the remainder of the study period. For this reason, a high rate of visit compliance during the postherpetic phase of the study was critical. Postherpetic neuralgia resolved almost two times faster in patients receiving famciclovir during acute zoster infection when compared with those receiving placebo (500-mg famciclovir group: hazard ratio, 1.7 [P = 0.02] and 750-mg famciclovir group: hazard ratio, 1.9 [P = 0.005]), which resulted in an approximate reduction of 2 months in the median duration of postherpetic neuralgia Figure 1, top). Among older patients (those 50 years of age), who are more at risk and in whom postherpetic neuralgia persists longer, pain resolved 2.6 times faster in those who were treated with famciclovir during acute zoster infection than those who received placebo [500-mg famciclovir group: P = 0.0044; 750-mg famciclovir group: P = 0.003], which resulted in a 3.5-month reduction in the median duration of postherpetic neuralgia Figure 1, bottom).

In conclusion, oral famciclovir at 500 mg or 750 mg administered three times daily for 7 days during acute zoster infection offers significant benefit to immunocompetent patients with herpes zoster by providing a well-tolerated convenient dosage regimen, an accelerated rate of lesion resolution, and a reduced duration of postherpetic neuralgia.

Appendix

The following are members of the Collaborative Famciclovir Herpes Zoster Study Group: Baylor College of Medicine, Houston, Texas: Suzanne Bruce, MD, Annette Harris, MD, Anne Epstein, MD, Lisa Lowry, MD, Howard Rubin, MD, John Dupuy, MD, Jay Hendricks, MD, Jeanette Greer, MD; Beverly Hills, California: Marvin Rapaport, MD; Bucks County Clinical Research, Morrisville, Pennsylvania: David J. Miller, DO, Brad S. Friedmann, DO, Randi M. Silverbrook, DO, Wayne Marley, MD; Clinical Study Center, Fort Myers and Cape Coral, Florida: Stephen R. Zellner, MD, David D. Michie, PhD, Felix Mestas, MD, Ronica Kluge, MD, Quinnon R. Purvis, MD, Nancy Schleider, MD, Juan Domingo, MD; Colorado Medical Research Center, Denver, Colorado: James M. Swinehart, MD, Kathy Williams, RN, Lisa Shultz, RN, Bonnie Rochambeaum, LPN; Deaconess Family Medicine, St. Louis, Missouri: James Nahlik, MD, Rick A. Barbarash, PharmD, David Campbell, MD, James Price, MD, Mark King, MD, Percival Moraleda, MD, Michael Toro, MD, Marta Mortensen, MD, Melinda Walker, MD, Bryan Steele, MD, Kathleen Castellanos, MD, Cheryl Miller, PharmD; Old Orchard Geriatrics and Family Medicine, St. Louis, Missouri: M. Dale Terrel, MD, Jessee Crane, MD; Southside Family Practice and Spurgeon Medical Group, St. Louis, Missouri: Robert Zink, MD, Scott Soerries, MD, Charles Nester, MD, Stephen Nester, MD; St. Louis Medical Research, St. Louis, Missouri: Glennon Fox, MD, Charles Crecelius, MD, Morton Singer, MD, Linda Stanton, MD; George Washington University Medical Center, Washington, D.C.: Mervyn L. Elgart, MD, Gayle Masri-Fridling, MD, Michael Noonan, MD, Pamela Scheinman, MD, M. Carol McNeely, MD, Maria Turner, MD; Georgetown University Medical Center, Washington, D.C.: Virginia I. Sulica, MD; Georgia Clinical Research Center, Atlanta, Georgia: Stephen J. Kraus, MD, Edmond I. Griffin, MD, D. Scott Karempelis, MD, Bette C. Potter, MD, Diane M. Smith, LPN; Harborview Medical Center, Seattle, Washington: Lawrence Corey, MD, Thomas Gill, MD; Henry Ford Hospital, Detroit, Michigan: Orlando G. Rodman, MD, Robert Norum, MD, Dennis Babel, PhD; Le Centre Hospitalier de l'Universite Laval, Ste. Foy, Quebec, Canada: Alain Martel, MD; Louisiana State University School of Medicine, Charity Hospital of Louisiana at New Orleans, Louisiana State University Lions Clinic, New Orleans, Louisiana: Lee T. Nesbitt Jr., MD, Brian D. Lee, MD, Donna G. Heitler, MD, Eric Hollabaugh, MD; Maplewood Family Practice, Winston-Salem, North Carolina: John B.R. Thomas, MD, Champ M. Jones, MD, Thomas B. Cannon, MD, Thomas W. Littlejohn III, MD, Keith V. VanZandt, MD, Gina Gottesman Shar, MS; Piedmont Research Associates, Winston-Salem, North Carolina: Sherrill D. Braswell Jr., MD, John G. Roach III, MD, Richard C. Worf, MD, Thomas W. Littlejohn, III, MD; Melbourne, Australia: Andrew Hellyar, MBBS; Minnesota Clinical Study Center, Fridley, Minnesota: H. Irving Katz, MD, Steven E. Prawer, MD, Jane S. Lindholm, MD, Ngo T. Hien, MD, Frederick S. Fish, MD, Jack C. Scott, MD, Steven Kempers, MD, M. Elizabeth Briden, MD; Montreal, Quebec, Canada: Michel Lassonde, MD, Claude Girard, MD, Victor Oliel, MD; Mt. Sinai Hospital, Toronto, Ontario: Andrew Simor MD, D. Low, MD, H. Velland, MD, W. Gold, MD; Nalle Clinic, Metrolina, Charlotte, North Carolina: John L. Benedum, MD, Ophelia E. Garmon-Brown, MD, W.S. Tucker Jr., MD, Kim Tam, MD, Ed Landis, MD, C. Whit Blount, MD, Selwyn Spangenthal, MD, Geoffrey Chapman, MD; Palm Beach Center for Clinical Investigation, West Palm Beach, Florida: Lee Fischer, MD, Holly W. Hadley, MD; St. Joseph's Health Centre of London, London, Ontario: Daniel Gregson, MD, Ole Hammerberg, MD; St. Michael's Hospital, Toronto, Ontario: Ignatius Fong, MD; Southern Illinois University School of Medicine, Memorial Medical Center, St. John's Hospital, Springfield, Illinois: Larry A. Von Behren, MD, Sergio Rabinovich, MD, Nancy Khardori, MD; SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania, Brentford, United Kingdom, Melbourne, Australia, and Oakville, Ontario: Robin Saltzman, MD, Ron Boon, BSc(Hons), CBiol, MIBiol, David Fitts, PhD, Charles Grier, PhD, David Griffin, Duncan McKay, Richard Birkenmaier, Simon Bishop, G. Lynn Marks, MD, Leslie Locke, PhD, Regina Jurewicz, RPh, Susan Weill, BSN, Thomas Mayewski, Carol Frazier, Ann Grossman, James MacDonald, Pam Murphy, Kathryn Stiede, Mary Beth Weigart, Mary Levidiotis, Marilyn Hosang, Jim Parsons; Sunnybrook Medical Centre, Toronto, Ontario: Anita R. Rachlis, MD; Toronto, Ontario: Gary D. Schachter, MD, Ricky K. Schachter, MD; University of Adelaide, Adelaide, South Australia: John Marley, MD, David Gordon, MD, Peter Hallsworth, PhD, Diane Markham, RN, Elizabeth Wilkinson, RN, M. Geraldine Smith, RN; University of Arizona Health Sciences Center, Tucson, Arizona: Kevin Welch, MD; University of California, San Diego, School of Medicine and Veterans Administration Medical Center, San Diego, California: Daniel Piacquadio, MD, Ann Fleming, RN; University of Cincinnati, Cincinnati, Ohio: Debra L. Breneman, MD, Bhakta V. Chetty, MD, Steven Manders, MD, Boris Lushniak, MD; University of Miami, Miami, Florida: Daniel Hogan, MD; University of Newcastle, Callaghan, New South Wales, Australia: Alexander Reid, MD, G. Tannock, MD, Nannette Dick, RN, Lorna Crossley, RN; University of Texas Medical Branch, Galveston, Texas: Stephen K. Tyring, MD, PhD, Robert Purvis, MD, Dayna Diven, MD, Neill Porter, MD; University of Texas Medical School at Houston, Houston, Texas: Adelaide A. Hebert, MD, John Bradford Bowden, MD, Keith Edward Schulze, MD; University Hospital, Saskatoon, Saskatchewan: Kurt E. Williams, MD, J.M. Conly, MD, C. Anderson, MD; Veterans Administration Medical Center, Minneapolis, Minnesota: Janellen Smith, MD, Nancy Krywonis, MD; Veterans Administration Medical Center, Sepulveda, California: Madalene C.Y. Heng, MD; Volunteers in Pharmaceutical Research, Bryan, Texas: Terry Jones, MD, Ted L. Rea, MD; Wenatchee Valley Clinic, Wenatchee, Washington: Richard Tucker, MD, Byron W. Lee, MD, Cooky Ogle; Westlake Village, California/Simi Valley, California: James S. Weintraub, MD; Westmead Hospital, Westmead, Australia: A. Cunningham, MBBS, MD, Dominic Dwyer, MBBS, David Holland, MBBS, Margaret Fordham, RN, Graeme Miller, MBBS, Terina Sylvester, RN; West Paces Ferry Hospital, Atlanta, Georgia: Steven I. Marlowe, MD, Mark L. Tanner, MD; Wheatridge, Colorado: Pasquale A. DiLorenzo, MD.