Ophthalmology. 2000 Feb;107(2):278-82.
Oral acyclovir for the management of herpes simplex virus keratitis in children.

Schwartz GS, Holland EJ.

University of Minnesota, Department of Ophthalmology, Minneapolis, USA.

PURPOSE: To evaluate the use of oral acyclovir in pediatric patients with herpes simplex virus (HSV) keratitis. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Seven pediatric patients seen at the University of Minnesota Hospitals and Clinics with herpes simplex virus (HSV) infectious epithelial keratitis between January 1992 and October 1998. Patient ages ranged from 6 weeks to 5 years at time of presentation with a median of 1.7 and mean of 1.9 years. INTERVENTION: All patients received oral acyclovir; six of seven patients also received topical antiviral medications. Three of seven patients had topical antiviral therapy fail before being placed on oral acyclovir, and the remaining four patients were placed on oral acyclovir primarily. RESULTS: All patients showed resolution of HSV infectious epithelial keratitis. Three patients have been maintained on prophylactic dosage of oral acyclovir because of recurrent disease or because they have been chronically treated with topical corticosteroids for immune stromal keratitis. All patients tolerated acyclovir well, and there were no adverse reactions. CONCLUSIONS: Oral acyclovir is useful in treating HSV infectious epithelial keratitis in pediatric patients. It is beneficial in treating infectious epithelial keratitis and prophylactically either while treating with topical corticosteroids for immune stromal keratitis or for preventing recurrent infectious epithelial keratitis.

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Ann Thorac Surg. 1993 Dec;56(6):1267-72; discussion 1272-3.
Cytomegalovirus disease after heart transplantation: is acyclovir prophylaxis indicated?

Elkins CC, Frist WH, Dummer JS, Stewart JR, Merrill WH, Carden KA, Bender HW Jr.

Department of Thoracic and Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-5734.

To determine the efficacy of acyclovir prophylaxis in preventing cytomegalovirus (CMV) disease after heart transplantation, the clinical course of 103 patients (ages, 0.1 to 62 years; mean age, 41.8 years; 87 males, 16 females) was analyzed. Active CMV infection (defined as a positive culture from any site or a fourfold increase in immunoglobulin G antibody titers) occurred in 64% (66/103) and clinical CMV disease (defined as pathologic evidence of CMV in tissue biopsy or a typical CMV syndrome with fever and two of the following: leukopenia, thrombocytopenia, atypical lymphocytes, and elevated liver function test results in a patient with CMV infection) occurred in 25% (26/103). Independent variables studied included acyclovir prophylaxis, duration of acyclovir use, duration and type of induction therapy, donor and recipient CMV status, total steroid dose at 3 and 6 months, azathioprine dose and cyclosporine level at 3 months, age, and sex. In a multivariate regression analysis, acyclovir prophylaxis was independently associated with freedom from CMV disease (p = 0.029). Positive donor CMV status (p = 0.025), higher total steroid dose at 3 months (p = 0.036), and lower azathioprine dose at 3 months (p = 0.047) were associated with higher occurrence of CMV disease. The use of antilymphocyte induction therapy was associated with an increased occurrence of active CMV infection (p = 0.022) but not CMV disease. The prophylactic administration of acyclovir reduced the occurrence of CMV disease after heart transplantation.

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J Inorg Biochem. 2001 Oct;86(4):677-80.
A calorimetric study of 3d metal ions-acyclovir interactions. The 2-hydroxyethoxymethyl group of acyclovir mimics the role of ribose in deoxy-guanosine and guanosine promoting the coordination through N(7).

Herrero LA, Cerro-Garrido JC, Terron-Homar A.

Departament de Quimica, Universitat de les Illes Balears, 07071, Palma de Mallorca, Spain.

The equilibrium constants and enthalpic values of metal acyclovir complexes have been determined by calorimetry for Co(II) (log K=0.96+/-0.05, DeltaH (kJ/mol)=-19.7+/-1.3), Ni(II) (log K=1.39+/-0.03, DeltaH (kJ/mol)=-21.5+/-1.0), Cu(II) (log K=1.83+/-0.03, DeltaH (kJ/mol)=-23.2+/-0.8) and Zn(II) (log K=0.71+/-0.06, DeltaH (kJ/mol)=-18.6+/-1.5). The equilibrium constants are similar to those of the divalent ions with guanosine and 2,9-dimethylpurine. By comparison with previous thermodynamic data, it can be shown that the 2-hydroxyethoxymethyl group promotes coordination through N(7) versus N(1) of the guanine ring for 3d metal ions. These results reveal that the 2-hydroxyethoxymethyl group placed on the purine ring of guanine in acyclovir causes a greater effect than that of the 9-methyl in purines and similar to or greater than that of the ribose moiety in guanosine. The 2-hydroxyethyoxymethyl group of acyclovir mimics the role of ribose in deoxy-guanosine and guanosine promoting a similar coordination chemistry (with very close log K and DeltaH values) for acyclovir, deoxy-guanosine and guanosine with divalent metals.

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J Med Chem. 1998 Jul 30;41(16):3001-7.
Antiviral activities of methylated nordihydroguaiaretic acids. 2. Targeting herpes simplex virus replication by the mutation insensitive transcription inhibitor tetra-O-methyl-NDGA.

Chen H, Teng L, Li JN, Park R, Mold DE, Gnabre J, Hwu JR, Tseng WN, Huang RC.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China, Organosilicon and Synthesis Laboratory, Department of Chemistry, National Tsing Hua University, Hsinchu, China-Taiwan.

We had previously reported that tetramethyl-O-NGDA (M4N), a synthetic derivative of the naturally occurring nordihydroguaiaretic acid (NDGA), is able to inhibit HIV Tat transactivation by blocking host Sp1 protein at the Sp1 cognate binding site on the HIV LTR promoter. The present studies were undertaken to examine whether M4N is able to inhibit the replication of herpes simplex virus (HSV), another Sp1-regulated virus. The results showed that in Vero cells, M4N inhibits at micromolar levels (IC50 = 43.5 microM) the expression of the herpes immediate early gene (alpha-ICP4), which is essential for HSV replication. An electrophoretic mobility shift assay, examining Sp1 binding to the alpha-ICP4 promoter, showed a significant inhibition of the control bands: 88% inhibition of the fast moving band (FMB) and 45% of the slow moving band (SMB), at 100 microM of drug concentration. Comparative studies between M4N and acycloguanosine (acyclovir, ACV) in cultured Vero cells revealed an interesting pattern in the drug sensitivity (IC50) and cytotoxicity (TC50) parameters. For M4N, the IC50 varied between 11.7 and 4 microM in 10 passages of HSV-1 and 4 passages of HSV-2 with no indication for a requirement of higher drug concentration. In contrast, for acyclovir, the IC50 increased from 7 microM in the first passage to 444 microM in the tenth passage of HSV-1, and >88 microM for the fourth passage of HSV-2, indicating a rapid build-up of drug resistance against acyclovir. While the selective index (SI), defined as the ratio: TC50/IC50, remained relatively constant for M4N; it dropped 60-fold for acyclovir in the endpoints of viral passages. Drug sensitivity for M4N toward the acyclovir-sensitive strain (sm44) and the acyclovir-resistant strain (ACV-10) of HSV-1 was similar, indicating no cross-resistance between M4N and acyclovir in their anti-HSV effects. These results may have an important clinical relevance since HSV has been shown to be a factor for spreading of HIV.

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Pharm Res. 1994 Feb;11(2):243-50.
Bile salt-fatty acid mixed micelles as nasal absorption promoters. III. Effects on nasal transport and enzymatic degradation of acyclovir prodrugs.

Shao Z, Mitra AK.

Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907-1336.

The absorption enhancement and presystemic degradation kinetics of a homologous series of acyclovir 2'-ester prodrugs were investigated in rats using the in situ nasal perfusion technique in the presence of bile salt-fatty acid mixed micelles. In vitro incubation studies indicated that nasal perfusate containing a mixed micellar solution generated higher ester-cleaving activity than isotonic phosphate buffer washings. Inhibitor screening and substrate specificity studies demonstrated the enzyme to be most likely carboxylesterase rather than true cholinesterase. The extent of prodrug cleavage by the carboxylesterase appears to correlate well with the substrate lipophilicity for esters with linear acyl chains. On the other hand, branching of the acyl side chain significantly retards acyclovir prodrug breakdown. To estimate the nasal epithelial membrane and cytoplasmic damaging effect caused by sodium glycocholate (NaGC)-linoleic acid (15 mM:5 mM) mixed micelles, the release profiles of 5'-nucleotidase (5'-ND), lactate dehydrogenase (LDH), and carboxylesterase in the nasal perfusate were measured as a function of time. The results indicated that the activities of all three enzymes resulting from the mixed micellar solution appeared to be significantly higher than those caused by 15 mM NaGC alone. The apparent nasal absorption rate constants of acyclovir and its butyrate, valerate, pivalate, and hexanoate ester prodrugs in mixed micellar solutions containing an esterase inhibitor (1 mM phenylmethylsulfonyl fluoride) were individually calculated. Without an inhibitor, lengthening of the linear acyl side chain of the prodrug resulted in greatly accelerated degradation coupled with moderate absorption improvement. The solubilities and micellar binding constants of acyclovir prodrugs were also determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8165183&dopt=Abstract acyclovir Zovirax