Pharmacokinetics of Acyclovir Suspension in Infants and Children

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1987, p /87/ $02.00/0 Copyright 1987, Americn Society for Microbiology Vol. 31, No. 11 Phrmcokinetics of Acyclovir Suspension in Infnts nd Children WAYNE M. SULLENDER,1 ANN M. ARVIN,'* PAMELA S. DIAZ,1 JAMES D. CONNOR,2 ROBERT STRAUBE,2 WAYNE DANKNER,2 MYRON J. LEVIN,3 STEPHEN WELLER,4 M. ROBERT BLUM,4 AND SHARON CHAPMAN4 Deprtment of Peditrics, Stnford University School of Medicine, Stnford, Cliforni ; Deprtment of Peditrics, University of Cliforni Sn Diego School of Medicine, Sn Diego, Cliforni ; Peditric Infectious Disese Section, University of Colordo Helth Sciences Center, Denver, Colordo ; nd Burroughs Wellcome Co., Reserch Tringle Prk, North Crolin Received 26 June 1987/Accepted 28 August 1987 Eighteen children from 3 weeks to 6.9 yers of ge were given n orl cyclovir suspension for herpes simplex or vricell-zoster virus infections. Thirteen ptients who were 6 months to 6.9 yers old received 600 mg/m2 per dose, nd three infnts nd two children less thn 2 yers old were given 300 mg/m2 per dose. The drug ws given four times dy, except to one infnt who ws treted with three doses dy. Among the 13 children who received the 600-mg/M2 dose, the mximum concentrtion in plsm (Cmx) ws p,g/ml (men + stndrd devition), the time to mximum concentrtion (Tmx) ws h, the re under the curve (AUC) ws p,g h/ml, nd the elimintion hlf-life (tl/2) ws h. The three infnts less thn 2 months of ge who received the 300-mg/M2 dose hd Cmx of 1.88 ± 1.11,g/ml, Tmx of 4.10 ± 0.48 h, n AUC of 6.54 ± 4.32,ugg h/ml, nd tl/2 of 3.26 ± 0.33 h. The cyclovir suspension ws well tolerted by young children. No dverse effects requiring discontinution of the drug occurred. Acyclovir [9-(2-hydroxyethoxymethyl)gunine] is nucleoside nlog which inhibits the repliction of herpes simplex virus (HSV) nd vricell-zoster virus (VZV). Acyclovir dministered prenterlly is effective for the tretment of neontl HSV infections, HSV encephlitis, nd genitl HSV infections (3, 25, 26). In immunosuppressed ptients, intrvenous cyclovir is useful for the therpy nd suppression of HSV infections nd for the therpy of VZV infections (6, 9, 10, 14, 18-20). The orl dministrtion of cyclovir is of benefit for the therpy nd suppression of genitl HSV infections in the norml dult host (2, 5, 9, 11, 17, 23) nd for the tretment nd suppression of recurrent mucocutneous HSV infections in immunocompromised ptients (14, 22). Phrmcokinetic informtion is vilble for cyclovir dministered intrvenously to dults nd children nd for the cpsule formultion given to dults (4, 18). The phrmcology of orl cyclovir tblets hs been investigted in children (12, 13). A liquid suspension formultion of the drug ws developed for children nd other ptients who cnnot ingest medictions in solid form. The purpose of our study ws to determine the phrmcokinetics nd tolernce of cyclovir suspension in children. (This work ws presented in prt t the 26th Interscience Conference on Antimicrobil Agents nd Chemotherpy, New Orlens, L., 28 September to 1 October 1986.) MATERIALS AND METHODS Ptients. Orl cyclovir suspension ws given to children less thn 7 yers of ge who hd HSV or VZV infections which were not of life-thretening nture. Ptients were excluded if their serum cretinine concentrtion ws greter thn 1.5 mgldl or if the serum bilirubin or liver trnsminse concentrtion ws more thn twice the norml vlue. Ptients who hd undergone resection of ny portion of the gstrointestinl trct, hd ny mlbsorption syndrome, or hd received rdition therpy to the bdomen within 3 * Corresponding uthor weeks before possible enrollment were lso excluded. The study ws pproved by the review committees responsible for reserch involving humn subjects t ech of the prticipting institutions. Informed consent ws obtined from the prent or gurdin of ech ptient. Drug dosing. Acyclovir (Zovirx) suspension (40 mg/ml) ws provided by the Burroughs Wellcome Co., Reserch Tringle Prk, N.C. The suspension ws given orlly or by nsogstric tube t 300 or 600 mg/m2 per dose. The doses were given four times dily t 0800, 1200, 1600, nd 2000 h for 5 to 7 dys. Thirteen children received 600 mg/m2 per dose nd five ptients, including the three infnts less thn 2 months of ge, received doses of 300 mg/m2. All ptients received four doses per dy except for one infnt who ws given 300 mg/m2 per dose three times per dy. Study design. Blood smples for determintion of cyclovir concentrtions in plsm were obtined immeditely before one of the doses nd 2 h fter the dose on study dy 2, 3, or 4. On the lst dy of cyclovir dministrtion, blood smples were tken just before nd t 1, 2, 3, 4, 6, nd 8 h fter the finl dose. Lbortory screening for toxicity ws done on entry, on dy 2, 3, or 4, nd on the dy of the finl dose. The lbortory tests performed were complete blood cell counts, including pltelet nd reticulocyte counts, determintion of concentrtions of electrolytes in serum, blood ure nitrogen, cretinine, lctte dehydrogense, glutmic oxlocetic trnsminse (SGOT), glutmic pyruvic trnsminse (SGPT), bilirubin, uric cid, mylse, nd lkline phosphtse, nd urinlysis. Determintion of cyclovir concentrtions in plsm. Smples were nlyzed for cyclovir concentrtions by rdioimmunossy, which hs been shown to be sensitive nd specific for cyclovir with miniml interference from metbolites (8, 15). Dt nlysis. The plsm cyclovir concentrtion-time dt were nlyzed by noncomprtmentl phrmcokinetic methods. The mximum concentrtion (Cmx) nd ssocited time point (Tmx) were determined bsed on the observed dt. The cyclovir elimintion hlf-life (t4/2) ws determined

2 VOL. 31, 1987 TABLE 1. Demogrphic informtion for ptients b~~~~~~~~~~~~ (in2)dies Sex Age Wt BSA Virl disese disese (kg) F 3 wk HSV suppression Neontl HSV F 4 wk HSV suppression Neontl HSV M 7 wk HSV suppression Neontl HSV F 0.5 yr Cutneous HSV Eczem F 0.6 yr Cutneous HSV Eczem M 0.9 yr HSV whitlow None F 1.5 yr Recurrent HSV Neontl HSV M 1.8 yr HSV whitlow None M 2.0 yr Herpes zoster Asthm F 2.3 yr ;59 Vricell post-vzig Leukemi M 3.5 yr Vricell Eczem F 3.9 yr Vricell postvccine Leukemi F 4.1 yr Vricell Eczem F 4.0 yr Retinitis Neon4tl HSV M 5.7 yr Vricell post-vzig Leukemi F 5.7 yr Vricell post-vzig Wilms' tumor F 6.2 yr Herpes zoster Leukemi M 6.9 yr Recurrent orl HSV Nephrosis F, Femle; M, mle. b BSA, Body surfce re. by log-liner lest-squres regression of the postbsorption portion of the concentrtion-time dt obtined fter the lst dose. The re under the,plsm concentrtion-time curve (AUC) resulting from the lst dose Ws estimnted by trpezoidl pproximtion, with extrpoltion to infinite time nd subtrction of tht portion of the AUC resulting from previous doses, by the following eqution: AUC = AUCG04 + Ct/kel Co/kel, whete AUC0 is the 8-h trpezoidl AUC, kei is the - terminl elimintion rte constnt, C, is the lst observed concentr,tion, nd Co is the concentrtion t the time of dministrtion of the finl dose. The clculted AUC is theoreticlly equl to the AUC tesulting from dministrtion of single dose. The cretinine clernce (CLcR) vlues were estimted by the following eqution: CLCR = 0.48 x (height of ptient/cre,tinine concentrtion in serum) (21, 24). RESULTS Ptients. Eighteen ptients, ged 3 weeks to 6.9 yers, prticipted in the study (Tble 1). Eight ptients hd VZV infections, nd 10 ptients hd HSV infections. Three term infnts, ged 3 to 7 weeks, were treted with cyclovir suspension beginning 2 dys fter the completion of course of intrvenous cyclovir for neontl HSV infections; cyclovir ws not detected in plsm before orl therpy ws initited. One of the five ptients with mlignncy hd ACYCLOVIR SUSPENSION PHARMACOKINETICS Time (Hours ofter th st io..) FIG. 1. Acyclovir concentrtions in plsm fter lst dose. The y xis represents cyclovir concentrtions (microgrms per milliliter; mens + stndrd devitions) in plsm, which were plotted ginst hours fter lst dose on the x xis for 13 ptients 6 months to 6.9 yers of ge who received 600 mg of cyclovir orl suspension per m per dose. herpes zoster, three hd receiyed vericell-zoster immune globulin (VZIG) fter chicken pox exposure but subseqdently developed vricell, nd one developed vricelllike rsh fter the dministrtion of n investigtionl vricell vccine. Concentrtions of cyclovir in plsm. The cyclovir concentrtions in plsm on dy 2, 3, or 4 nd fter the lst dose re shown in Tble 2. For concentrtions determined on dy 2, 3, or 4, the predose vlues represent ttough concentrtions present either 4 or 12 (overnight) h fter the preceding dose. No significnt differences were observed between the men cyclovir concentrtions in plsm fter the lst dose for ptients less thn 4 yers of,ge nd those, from 4 to 7 yers old, who received doses of 600 mg/in2. Th time profile of men cyclovir concentrtions in plsm fter the lst dose for ll ptients who received the 606_mg/m2 dose legimen is shown in Fig. 1. Among ptients'receiving 300 m,g/im2, the three infnts less thn 2 months of ge hd higher men concentrtions 2 to 8 h fter the lst dose thn did the two children who were 1.5 nd 1.8 yers of ge (Tble 2). Phrmcokinetic nlysis. Phrmcokinetic prmeters determined from individul ptient dt fter the lst dose re TABLE 2. Acyclovir concentrtions in plsm Acyclovir concn (p.g/ml [men ± SD]) Age (mg/) Dy 2, 3, or 4 Before lst Time (h) fter lst dose Bo-fore 2 h dose mo-4 yr (7)b ± ± ± ± ± ± ± ± , ± yr (6)C ± ± ± ± ± ± ± ± ± 0.20 Men ± SD ± ± ± ± ± ± ± ± ± 0.17 (13) 6 mo- 7 yr <2 mo (3) ± ± ± ± ± ± ± ± ± mo-4 yr (2) ± ± ± ± ± ± ± ± ± 0.02 Smples were drwn on dy 2, 3, or 4 just before nd 2 h fter dose 1, 2, 3, or 4. bone ptient received n extr dose oh the lst dy 3.5 h fter the scheduled lst dose; 4- to 8-h points were excluded from the men. c Dt for one ptient for whom there were substntil devitions from the protocol dosing regimen were excluded from the mens.

3 1724 SULLENDER ET AL. presented for ech ge group nd dosge regimen in Tble 3. The men vlues for ll ptients receiving 600 tng/m2 per dose were s follows: Cmx, ,ug/ml (men stndrd devition); Tmx, 3.0 ± 0.86 h; AUC, 5.56 ± 2.17 Kg. h/ml; nd t1/2, 2.59 ± 0.78 h. The men phrmcokinetic vlues were sitilr for children between 6 months nd 4 yers of ge nd children over 4 yers old receiving the 600-mg/M2 dose. Three infnts less thn 2 months of ge nd two children between 2 months nd 4 yers of ge were given cyclovir suspension t 300 mg/m2 per dose. The three infnts who were less thni 2 months of ge chieved higher men Cmx, 1.88,ug/ml, nd hd somewht longer men t112, 3.26 h, thn did the older children receiving the sme or higher dose (Tble 3). By using interpoltion nd superimposition of men dt, the stedy-stte cyclovir concentrtions in plsm were simulted for the 600-mg/M2 dose (Fig. 2). The expected pek cyclovir concentrtions fter four consecutive doses given t 4-h intervls were pproximtely 0.9, 1.3, 1.4, nd 1.5 p.g/ml fter successive doses during the dy. Adverse rections. Three ptients experienced dverse clinicl rections which were self-limited nd did not require discontinution of the drug. The dverse effects were mild dirrhe, mild vomiting, or profuse diphoresis. Minor vritions were observed in the heptic trnsminse levels in seven ptients, but five ptients hd elevted trnsminse levels before cyclovir ws begun. None of the ptients hd SGOT or SGPT greter thn twice the norml vlue. Preexisting hemtologic bnormlities in ptients with mlignncy nd nephrotic syndrome persisted during the study, s did nemi in the infnt with eczem. The older ptient with eczem hd decline in hemoglobin from 12.1 to 10.0 g/di during the study. No significnt chnges were observed in the CLCR vlues clculted from the cretinine concentrtions in serum obtined on dy 1, dy 2, 3, or 4, nd the lst study dy. No bnormlities in blood ure nitrogen or cretinine developed during the study. The observed lbortory bnormlities were not considered to be drug relted, nd none necessitted discontinuing the study drug. DISCUSSION Approximtely 20% of orl cyclovir given to dults is bsorbed. Adults tking cyclovir cpsules (200 mg every 4 h) hd Cmx of 0.5,ug/ml. A 200-mg dose is equivlent to 115 mg/m2 for n verge dult mle. A dose of 400 mg every 4 h produced Cmx of 1.2,ug/ml (4). The pek plsm concentrtion ws 1.82 p.g/ml when cyclovir ws given in tblet form to children t dose of 600 mg/i2 (13). In our study, children who received 600 mg of cyclovir suspension 3- e ANTIMICROB. AGENTS CHEMOTHER. TIME (HOURS) FIG. 2. Simulted stedy-stte cyclovir concentrtions in plsm. The simulted stedy-stte cyclovir concentrtions (microgrms per milliliter) in plsm plotted on the y xis were obtined by interpoltion nd superimposition of the men dt for 13 ptients 6 months to 6.9 yers of ge who received 600 mg of cyclovir orl suspension per ni2 per dose. The times indicted on the x xis re bsed on four doses given every 4 h during the dy (i.e., t h 0, 4, 8, nd 12). per m2 per dose hd men vlues for Cmx of 0.99,ug/ml nd t1/2 of 2.59 h. On the bsis of body surfce re, these children received the equivlent of five times the dult orl dose of 200 mg, but the pek concentrtion in plsm ws only twofold higher thn the pek concentrtion in plsm in dults. Thus, with identicl dosge regimens, the pek concentrtion in plsm in children would be bout 40% of the expected pek level in dults. This difference cn be explined in prt by the fct tht the Cmx in the present study ws determined fter dose given 12 h fter the previous dose. In the dult phrmcokinetic study, the Cmx ws mesured t stedy stte in subjects receiving the drug every 4 h in ech 24-h period. The lower pek concentrtions in children probbly lso reflect slower bsorption of the drug from the suspension compred with the rte of bsorption fron cpsules given to dults. In contrst to the difference in Cmx, the dose-normlized AUC in children given cyclovir suspension ws pproximtely 75% of tht fter cpsule dministrtion to dults. The men Cmx fter 300-mg/m2 dose nd the AUC were proportiontely less thn the vlues for 600 mg/m2. Only three infnts less thn 2 months of ge received orl cyclovir suspension. However, the dministrtion of the TABLE 3. Noncomprtmentl nlysis of cyclovir concentrtions in plsm fter lst dose of orl cyclovir suspension Dose AUC CLCR (mi/min Age group (n) (mg/ds) Cm. (Gjg/ml) T... (h) (AUCh/mi) tl/2 (h) per 1.73mi2) 6 mo-4 yr (7) ± ± ± ± ± yr (6)b ± ± ± ± ± 19 Men ± SD (13) 6 mo-7 yr ± ± ± ± ± 24 <2 mo (3)c ± ± ± ± ± 14 6 mo-a yr (2) ± ± ± ± 8.5 One ptient received n extr dose 3.5 h fter the lst scheduled dose; the AUC ws excluded from the men clcultion. b One ptient ws not ihcluded in the men clcultions becuse of substntil devitions from the protocol dose schedule. The elimintion rte ws indeterminble for one ptient who hd identicl concentrtions t 3.0 h nd t the lst smpling time (8.0 h). Therefore, Tmx, AUC, nd tl2 were not included. re not reported; in this instnce, the Tmx ws set equl to c The dt for one ptient were insufficient for determintion of the kei; therefore, AUC nd tl/2 the men t consecutive time points (3.083 nd 4.167) t which Cmx occurred.

4 VOL. 31, mg/M2 dose produced higher Cmx nd longer t112. The estimted CLCR in these ptients ws 50 ml/min per 1.73 m2, which reflects immture renl function in this ge group nd probbly ccounts for the higher concentrtions of cyclovir in plsm. As ws expected, the concentrtions of cyclovir in plsm fter its orl dministrtion to children were significntly lower thn those observed with intrvenous therpy. Children given doses of 250 mg of cyclovir per m2 intrvenously hd men Cmx of 10.3 ± 4.0 jig/ml. Doubling the dose to 500 mg/m2 produced men Cmx of 20.7 ± 5.0,ug/ml, nd the overll men t112 for children ws 2.52 ± 1.04 h (1). Neontes receiving 10 mg/kg per dose hd men pek cyclovir level of 13.9 ± 4.2 jig/ml, with t112 of 3.78 ± 1.21 h (7). No serious toxicity ws observed in our study, which ws predictble since the higher cyclovir concentrtions in plsm fter intrvenous dministrtion were tolerted well. The ntivirl ctivity of cyclovir hs been determined by in vitro ssys, but extrpoltion to in vivo inhibitory effect must be mde with cution. A number of fctors my lter the in vitro effects of the drug upon virl repliction, nd the correltion of specific drug concentrtions in plsm with the clinicl outcome hs not been proved. Acyclovir concentrtions of 0.01 to 0.7 ug/lml inhibit HSV type 1 cytopthic effects by 50%, nd concentrtions of 0.01 to 3.2 jig/ml inhibit HSV type 2. The in vitro inhibition of VZV occurs t 0.3 to 10.8 plg/ml (18). Thus, the drug concentrtions required to inhibit mny VZV isoltes my be greter thn the Cmx of 0.99 pg/ml which ws obtined in children given the orl suspension of cyclovir. The present study provides the phrmcologic bsis for investigting the efficcy of orl cyclovir suspension for the tretment of herpesvirus infections in peditric ptients. Plcebo-controlled clinicl trils will be necessry to determine whether the pek concentrtions in plsm of pproximtely 1.0 jig/ml obtined in our ptients receiving the 600-mg/M2 dose re dequte for the tretment of infections cused by VZV nd some strins of HSV. Although mny ptients with non-life-thretening herpesvirus infections my benefit from orl suspension therpy, these phrmcokinetic dt suggest tht orl cyclovir therpy is not pproprite for the initil tretment of neontl HSV infections or other severe herpesvirus infections in children. ACKNOWLEDGMENT This study ws supported by Burroughs Wellcome Co., Reserch Tringle Prk, N.C. LITERATURE CITED 1. Blum, M. R., S. H. T. Lio, nd P. de Mirnd Overview of cyclovir phrmcokinetic disposition in dults nd children. Am. J. Med. 73: Bryson, Y. J., M. Dillon, M. Lovett, G. Acun, S. Tylor, J. D. Cherry, B. L. Johnson, E. Weismeir, W. Growdon, T. Cregh- Kirk, nd R. Keeney Tretment of first episodes of genitl herpes simplex virus infection with orl cyclovir: rndomized double-blind controlled tril in norml subjects. N. Engl. J. Med. 308: Corey, L., K. M. Fife, J. K. Benedetti, C. Winter, A. Fhnlnder, J. D. Connor, M. A. Hintz, nd K. K. Holmes Intrvenous cyclovir for the tretment of primry genitl herpes. Ann. Intern. Med. 98: de Mirnd, P., nd M. R. Blum Phrmcokinetics of orl cyclovir fter intrvenous nd orl dministrtion. J. Antimicrob. Chemother. 12(Suppl. B): Dougls, J. M., C. Critchlow, J. Benedetti, G. J. Mertz, J. D. ACYCLOVIR SUSPENSION PHARMACOKINETICS 1725 Connor, M. A. Hintz, A. Fhnlnder, M. Remington, C. Winter, nd L. Corey A double-blind study of orl cyclovir for suppression of recurrences of genitl herpes simplex virus infection. N. Engl. J. Med. 310: Hnn, I. M., H. J. Prentice, H. J. Blcklock, M. G. R. Ross, D. Brigden, A. E. Rosling, C. Burke, D. H. Crwford, W. Brumfitt, nd A. V. Hoffbrnd Acyclovir prophylxis ginst herpes virus infections in severely immunocompromised ptients: rndomized double blind tril. Br. Med. J. 287: Hintz, M., J. D. Connor, S. A. Spector, M. R. Blum, R. E. Keeney, nd A. S. Yeger Neontl cyclovir phrmcokinetics in ptients with herpes virus infections. Am. J. Med. 73: Hintz, M., R. P. Quinn, S. A. Spector, R. E. Keeney, nd J. D. Connor Field use nd vlidtion of the rdioimmunossy for cyclovir, p In J. D. Nelson nd C. Grssi (ed.), Current chemotherpy nd infectious disese, vol. 2. Americn Society for Microbiology, Wshington D.C. 9. Mertz, G. J., C. W. Critchlow, J. Benedetti, R. C. Reichmn, R. Dolin, J. Connor, D. C. Redfield, M. C. Svoi, D. D. Richmn, nd D. L. Tyrrell Double-blind, plcebo-controlled tril of orl cyclovir in first-episode genitl herpes simplex virus infection. J. Am. Med. Assoc. 252: Meyers, J. D., J. C. Wde, C. D. Mitchell, R. Serl, P. S. Leitmn, D. T. Durck, M. J. Levin, A. C. Segrety, nd H. H. Blfour Multicenter collbortive tril of intrvenous cyclovir therpy for tretment of mucocutneous herpes simplex infection in the immunocompromised host. Am. J. Med. 73: Mindel, A., I. V. Weller, A. Fherty, S. Sutherlnd, D. Hindley, A. P. Fiddin, nd M. W. Adler Prophylctic orl cyclovir in recurrent genitl herpes. Lncet ii: Novelli, V. M., W. C. Mrshll, J. Yeo, nd G. D. McKendrick Acyclovir dministered perorlly in immunocompromised children with vricell-zoster infections. J. Infect. Dis. 149: Novelli, V. M., W. C. Mrshll, J. Yeo, nd G. D. McKendrick High-dose orl cyclovir for children t risk of disseminted herpesvirus infections. J. Infect. Dis. 151: Pettersson, E., T. Hovi, J. Ahonen, A. P. Fiddin, K. Slmel, K. Hockerstedt, B. Eklund, E. von Willebrnd, nd P. Hyry Prophylctic orl cyclovir fter renl trnsplnttion. Trnsplnttion 39: Prober, C. G., L. E. Kirk, nd R. E. Kenney Acyclovir therpy of chickenpox in immunosuppressed children- collbortive study. J. Peditr. 101: Quinn, P. P., P. de Mirnd, L. Gerld, nd S. S. Good A sensitive rdioimmunossy for the ntivirl gent BW248U [9-(2-hydroxyethoxymethyl)gunine]. Anl. Biochem. 98: Reichmn, R., G. J. Bdger, G. J. Mertz, L. Coury, D. D. Richmn, J. D. Connor, D. Redfield, M. C. Svoi, M. N. Oxmn, nd Y. Bryson Tretment of recurrent genitl herpes simplex infections with orl cyclovir: controlled tril. J. Am. Med. Assoc. 251: Richrds, D. M., A. A. Crmine, R. N. Brogden, R. C. Heel, T. M. Speight, nd G. S. Avery Acyclovir. A review of its phrmcodynmic properties nd therpeutic efficcy. Drugs 26: Srl, R., R. F. Ambinder, W. H. Burns, P. A. Angelopulos, D. E. Griffin, P. J. Burke, nd P. S. Leitmn Acyclovir chemoprophylxis ginst herpes simplex virus infections in ptients with leukemi. A rndomized, double-blind, plcebocontrolled study. Ann. Intern. Med. 99: Srl, R., W. H. Burns, 0. L. Lskin, G. W. Sntos, nd P. S. Lietmn Acyclovir prophylxis of herpes-simplex-virus infections: rndomized, double-blind controlled tril in bonemrrow-trnsplnt recipients. N. Engl. J. Med. 305: Schwrtz, G. J., L. G. Feld, nd D. L. Lngford A simple estimte of glomerulr filtrtion in full-term infnts during the first yer of life. J. Peditr. 104: Shepp, D. H., B. A. Newton, P. S. Dndliker, N. Fluornoy, nd J. D. Myers Orl cyclovir for mucocutneous herpes simplex virus infections in immunocompromised mrrow trns-

5 1726 SULLENDER ET AL. plnt recipients. Ann. Intern. Med. 102: Strus, S. E., H. E. Tkiff, M. Seidlin, S. Bchrch, L. Lininger, J. J. Di GiQvnnA, K. A. Western, H. A. Smith, S. N. Lehrmn, nd T. Cregh-Kirk Suppression of frequently recurring genitl herpes: plcebo-controlled double-blind tril of orl cyclovir. N. Engl. J. Med. 310: Trub, S. L., nd C. E. Johnson Comprison of methods of estimting cretinine clernce in children. Am. J. Hosp. ANTIMICROB. AGENTS CHEMOTHER. Phrm. 37: Whitley, R. J., C. A. Alford, M. S. Hirsch, R. T. Schooley, J. P. Luby, F. Aoki, D. Hnley, A. J. Nhmis, S. J. Soong, nd the NIAID Collbortive Antivirl Study Group Vidrbine versus cyclovir therpy in herpes simplex encephlitis. N. Engl. J. Med. 314: Whitley, R. J., nd C. Hutto Neontl herpes simplex virus infections. Peditr. Rev. 7: