PubMed · 14626128
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Ken-ichi Shimada, Kiyoshi Maeda. 2003. [Herpes simplex encephalitis].. https://pubmed.ncbi.nlm.nih.gov/14626128/
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Nucleoside analogs used in antiviral therapies need to be phosphorylated to their tri-phospho counterparts in order to be active on their cellular target. Human phosphoglycerate kinase (hPGK) was recently reported to participate in the last step of phosphorylation of cytidine L-nucleotide derivatives [Krishnan PGE, Lam W, Dutschman GE, Grill SP, Cheng YC. Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents. J Biol Chem 2003;278:36726-32]. In the present work, we extended the enzymatic study of human PGK specificity to purine and pyrimidine nucleotide derivatives in both D- and L-configuration. Human PGK demonstrated catalytic efficiencies in the 10(4)-10(5)M(-1)s(-1) range for purine ribo-, deoxyribo- and dideoxyribonucleotide derivatives, either in D- or L-configuration. In contrast, it was poorly active with natural pyrimidine D-nucleotides (less than 10(3)M(-1)s(-1)). Pyrimidine L-enantiomers, which are promising therapeutic analogs against B hepatitis, were 2-25 times better substrates than their D-counterparts. The broad specificity of substrate of human PGK suggests that this enzyme may be involved in the cellular activation of several antiviral nucleoside analogs including dideoxyinosine, acyclovir, L-2'-deoxycytosine and L-2'-deoxythymidine.
Low oral bioavailability continues to drive research toward identifying novel approaches to enhance drug delivery. Over the past few years, emphasis on the use of absorption enhancers has been overwhelming despite their major adverse effects. Zonula occludens toxin (Zot) was recently established as a safe and effective absorption enhancer, reversibly opening the tight junctions for hydrophilic markers and hydrophobic drugs across the small intestine and the blood brain barrier. DeltaG, the biologically active fragment of Zot, was isolated and shown to increase the in vitro transport and in vivo absorption of paracellular markers. The objective of this study was to examine the effect of DeltaG on the oral bioavailability of low bioavailable therapeutic agents. Jugular vein cannulated Sprague-Dawley rats were randomly assigned to receive the following treatments intraduodenally (ID): [(3)H]cyclosporin A, [(3)H]ritonavir, [(3)H]saquinavir, or [(3)H]acyclovir at (120 microCi/kg) alone, with protease inhibitors (PIs), or with DeltaG (720 microg/kg)/PI. Serial blood samples were collected, and plasma was analyzed for radioactivity. After ID administration with DeltaG/PI, C(max) significantly (p < 0.05) increased over a range of 197 to 5700%, whereas area under the plasma concentration time curve displayed significant increases extending over a range of 123.8 to 4990.3% for the investigated drugs. DeltaG significantly increased the in vivo oral absorption of some low bioavailable drugs in the presence of PI. This study suggests that DeltaG-mediated tight junction modulation, combined with metabolic protection, may be used to enhance the low oral bioavailability of certain drugs when administered concurrently.
BACKGROUND: Valacyclovir exhibits better oral absorption and higher, more prolonged serum concentrations than oral acyclovir. The efficacy of valacyclovir and acyclovir on genital herpes simplex virus (HSV) shedding was assessed in a double-blind, 3-period crossover trial. METHODS: Sixty-nine immunocompetent participants with genital HSV-2 received oral valacyclovir, acyclovir, and matching placebo in random order for 7-week periods. Participants provided daily genital mucosal swabs for HSV detection by viral culture and polymerase chain reaction (PCR). RESULTS: HSV was detected at least once in 62 (90%) participants by culture and in 68 (98%) by PCR. During placebo, the total HSV shedding rate was 15.4% of days by culture (PCR, 40.2%); the subclinical shedding rate was 6.6% by culture (PCR, 27.1%). Both antivirals were associated with lower HSV shedding by culture (relative risk [RR], 0.03 [95% confidence interval [CI], 0.01-0.07] for valacyclovir and RR, 0.05 [95% CI, 0.03-0.10] for acyclovir) and PCR (RR, 0.18 [95% CI, 0.12-0.26] for valacyclovir and RR, 0.20 [95% CI, 0.15-0.28] for acyclovir), compared with placebo. No significant differences in frequency and quantity of HSV were detected by PCR between the valacyclovir and acyclovir arms. CONCLUSIONS: Although the suppression of viral replication is not complete, valacyclovir and acyclovir are highly effective in suppressing the frequency and quantity of genital HSV shedding.