J Pharm Sci. 2002 Dec;91(12):2593-8.
Preliminary pharmacokinetic study of different preparations of acyclovir with beta-cyclodextrin.

Luengo J, Aranguiz T, Sepulveda J, Hernandez L, Von Plessing C.

Department of Pharmacy, Faculty of Pharmacy, Casilla 237, Universidad de Concepcion, Concepcion, Chile.

Acyclovir has absorption problems, because of its low solubility and/or its saturable absorption mechanism, that take place in the small intestine in a passive, variable, and incomplete manner. The oral bioavailability of acyclovir is thereby affected and reaches only 15-30%. The purpose of this study was to investigate the possibility of increasing the oral availability of acyclovir by forming inclusion complexes of acyclovir with beta-cyclodextrin. Acyclovir, its complex (1:1) with beta-cyclodextrin (acyclovir-beta-cyclodextrin complex), and a 50:50 mixture of acyclovir and the inclusion complex (acyclovir/complex mixture) as an aqueous suspension were administered intraintestinally to male Sprague-Dawley rats in doses equivalent to an acyclovir dose of 75 mg/kg. Sequential samples of plasma were taken by microdialysis. The samples were analyzed by high-performance liquid chromatography with ultraviolet detection. Plasma concentration versus time curves show that the complex and the mixture of acyclovir/complex have a higher bioavailability and a pharmacokinetic profile than that of the drug itself. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2593-2598, 2002

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12434403&dopt=Abstract acyclovir Zovirax




J Med Assoc Thai. 2002 Oct;85(10):1121-9.
Bioequivalence study of generic acyclovir compared with the brand name acyclovir.

Rojanasthien N, Teekachunhatean S, Kumsorn B, Chaichana N, Hay YK.

Division of Clinical Pharmacology, Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

The bioequivalence study of 200-mg generic acyclovir was conducted in healthy males. The reference Zovirax and the test Zevin were administered as a single oral dose after an overnight fast in a two-period, crossover design separated by 1 week. Serial blood samples were collected over a period of 24 hours. Plasma acyclovir concentrations were determined by HPLC and the pharmacokinetic parameters were analyzed by non-compartmental analysis. RESULTS: The t 1/2 for the test (4.5 +/- 2.4 h) and Zoviraxl (3.9 +/- 2.6 h) were comparable. The analysis of variance was carried out and the median Tmax (1.50 h) for the test was not statistically difference from Zovirax. The mean (90% CI) of the AUC0-infinity and the Cmax ratios for (Test/reference) were 0.95 (0.83-1.09) and 0.95 (0.83-1.10), respectively. These values fell within the bioequivalence criteria of 0.80-1.25, thus it was concluded that Zevin and Zovirax were bioequivalence.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12501905&dopt=Abstract acyclovir Zovirax




Arch Intern Med. 2003 Jan 13;163(1):76-80.
Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics.

Reyes M, Shaik NS, Graber JM, Nisenbaum R, Wetherall NT, Fukuda K, Reeves WC; Task Force on Herpes Simplex Virus Resistance.

Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.

BACKGROUND: Genital herpes is epidemic in the United States; long-term acyclovir therapy is common; and long-term use of antimicrobials in suppressive doses favors development of resistance. OBJECTIVE: To determine the prevalence of and risk factors for acyclovir-resistant genital herpes. METHODS: We identified and attempted to enroll all patients 18 years or older with suspected genital herpes who attended 22 sexually transmitted disease and human immunodeficiency virus (HIV) clinics in the United States between October 1996 and April 1998. We conducted standardized interviews of all consenting patients. Lesions were cultured, and isolates were typed as herpes simplex virus (HSV) 1 or HSV-2 and tested for acyclovir sensitivity (using a 50% inhibitory concentration of 2 microg/mL) by plaque reduction, which was independently confirmed. RESULTS: Herpes simplex virus was isolated from 2088 of 3602 patients, and 90.2% of isolates were HSV-2. Fifteen isolates, all HSV-2, were acyclovir resistant. Three (0.18%) of 1644 HIV-negative patients had acyclovir-resistant isolates (95% confidence interval [CI], 0.04%-0.5%); resistance was associated with oral (P<.006) and topical (P<.001) acyclovir use. Twelve (5.3%) of 226 HIV-positive patients yielded resistant HSV isolates (95% CI, 2.8%-9.1%); resistance was associated with oral acyclovir use (P<.001), duration of the current episode (P<.001), history of recurrent genital herpes (P<.01), and low CD4 cell count (P<.05). CONCLUSIONS: In the 15 years following licensure of acyclovir, resistance to the drug remains low among immunocompetent patients. However, 5% of HIV-positive patients had resistant HSV-2 isolates. Continued surveillance is essential to monitor changes in acyclovir resistance and to characterize the clinical and public health importance of acyclovir-resistant HSV.

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J Control Release. 2003 Jan 17;86(2-3):279-92.
Prodrugs of purine and pyrimidine analogues for the intestinal di/tri-peptide transporter PepT1: affinity for hPepT1 in Caco-2 cells, drug release in aqueous media and in vitro metabolism.

Thomsen AE, Friedrichsen GM, Sorensen AH, Andersen R, Nielsen CU, Brodin B, Begtrup M, Frokjaer S, Steffansen B.

Department of Pharmaceutics, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark.

A general drug delivery approach for increasing oral bioavailability of purine and pyrimidine analogues such as acyclovir may be to link these compounds reversibly to stabilized dipeptide pro-moieties with affinity for the human intestinal di/tri-peptide transporter, hPepT1. In the present study, novel L-Glu-Sar and D-Glu-Ala ester prodrugs of acyclovir and 1-(2-hydroxyethyl)-linked thymine were synthesized and their affinities for hPepT1 in Caco-2 cells were determined. Furthermore, the degradation of the prodrugs was investigated in various aqueous and biological media and compared to the corresponding hydrolysis of the prodrug valaciclovir. Affinity studies showed that the L-Glu-Sar prodrugs had high affinity for hPepT1 (K(i) approximately 0.2-0.3 mM), whereas the D-Glu-Ala prodrugs had poor affinity (K(i) approximately 50 mM). The pH-rate profiles of the prodrugs D-Glu[1-(2-hydroxyethyl)thymine]-Ala and L-Glu[acyclovir]-Sar showed specific base catalyzed degradation at pH above 4.5 and 5.5, respectively. This implicates that the degradation rates at pH approximately 7.4 (t(1/2) approximately 3.5 and 5.5 h) are approximately 25 times faster than at upper small intestinal pH approximately 6.0. In 10% porcine intestinal homogenate and 80% human plasma the half-lives of the L-Glu-Sar prodrugs were approximately between 45 and 90 min indicating a limited enzyme catalyzed degradation. In contrast, valaciclovir underwent extensive enzyme catalyzed hydrolysis in 10% porcine intestinal homogenate (t(1/2) approximately 1 min). In conclusion, L-Glu-Sar may potentially function as pro-moiety for purine and pyrimidine analogues, where release of parent compound primarily is controlled by a specific base catalyzed hydrolysis. Acyclovir is quantitatively released at the relevant pH 7.4, whereas the 1-(2-hydroxyethyl)-linked thymine is released instead of the parent compound thymine.

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iss.it

The efficacy of anti-herpetic drugs in decreasing HIV disease progression has not been clarified. We studied a cohort of 126 HIV-positive individuals with known date of seroconversion who were HSV-2-seropositive to determine if progression to AIDS was influenced by treatment with acyclovir. In the multivariate analysis, being homosexual and low CD4 count were associated with a faster progression to AIDS, whereas treatment with acyclovir showed a 37.0% protective effect compared to those who did not receive it when antiretroviral treatment was not included in the model. When including antiretroviral therapy, the protective effect of acyclovir decreased to 9.0% and that of antiretroviral therapy was 43.0% for monotherapy and 36.0% for double therapy, suggesting that most of the protective effect of acyclovir in the previous model was due to antiretroviral therapy. In conclusion, treatment with acyclovir does not seem to prolong significantly survival to AIDS among HIV-positive individuals who are HSV-2-infected.

Online pharmacy ref source - acyclovir: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12553484&dopt=Abstract acyclovir Zovirax