PubMed · 9141815
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
H Singh. 1996. Acyclovir in chickenpox.. https://pubmed.ncbi.nlm.nih.gov/9141815/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Xenopus laevis oocytes were used as a gene expression system to characterize the carrier-mediated transport of valacyclovir (vacv), the L-valine ester prodrug of the acyclic nucleoside acyclovir (acv). A significant increase in the uptake of [3H]vacv by Xenopus laevis oocytes injected with human intestinal peptide transporter (hPepT1) cRNA compared to the uptake by water injected oocytes indicated that vacv was translocated by hPepT1. Vacv uptake was found to be concentration dependent, saturable (K(m) = 5.94 +/- 1.91 mM and Jmax = 1.68 +/- 0.25 nmoles/hr/oocyte), pH dependent, and inhibited by various known substrates of hPepT1 but not by acv, valine or pentaglycine. Vacv also inhibited the uptake of 14C-glycylsarcosine, a known substrate of hPepT1, in a concentration-dependent manner (Ki = 4.08 +/- 1.02 mM). These results demonstrate that human intestinal peptide transporter hPepT1 has broad specificity since it recognizes vacv as a substrate even though it lacks a typical peptide bond.
HISTORY AND CLINICAL FINDINGS: A previously healthy 26-year-old man complained of gradually increasing headache after an attack of flu. After 4 days an erythema with papules but no blisters was noted in the area of distribution of the left 10th thoracic nerve. As a child he had varicella (chickenpox) without complications. INVESTIGATIONS: Lymphocytic pleocytosis and evidence of an abnormal blood-brain barrier were noted in cerebrospinal fluid (CSF). Serology for varicella zoster virus revealed an IgG titre of > 7400 IU/l in serum and 21 IU/l in CSF. The corresponding IgM titres were negative. TREATMENT AND COURSE: The headaches and cutaneous changes regressed under i.v. treatment with acyclovir, 10 mg/kg body weight, 3 x daily for 10 days. Repeat CSF examination after 10 days showed merely minimal residual changes of inflammation. CONCLUSION: This case illustrates the risk of severe neurological complications of herpes zoster infection. A seemingly minor rash with headache must be correctly diagnosed and immediate high-dosage acyclovir treatment instituted to prevent life-threatening and severe complications of herpes zoster meningitis or encephalitis.
Enzyme-prodrug therapy using ganciclovir and herpes simplex virus-thymidine kinase (HSV-TK) has demonstrated excellent antitumor activity in many different types of malignant cells. Previously, we noted that ganciclovir was substantially more cytotoxic than other HSV-TK substrates. Therefore, we embarked on a study to determine the basis for the superior cytotoxicity of ganciclovir. In U251tk human glioblastoma cells that stably express HSV-TK, ganciclovir elicited a >4 log cell kill instead of the < or =1.5 log cell kill mediated by two other HSV-TK substrates, 1-beta-D-arabinofuranosylthymine (araT) and acyclovir. Study of the metabolism of these drugs demonstrated that acyclovir was poorly phosphorylated to its active triphosphate with DNA incorporation below the limit of detection, which may explain the < 1 log cell kill in these cells. Lower levels of ganciclovir triphosphate accumulated compared with araT triphosphate (araTTP) under conditions that induced < or =1 log cell kill (67 versus 1235 pmol/10(7) cells, respectively), and the half-life for the triphosphate of ganciclovir was shorter than that of araT (terminal half-lives of 15 and 41 h, respectively). Incorporation of ganciclovir monophosphate into DNA was less than that of araT monophosphate, and both analogues were retained in DNA for > or =48 h. Thus, the superior cytotoxicity of ganciclovir was not due to enhanced metabolism to active forms. Highly cytotoxic concentrations of ganciclovir produced only weak inhibition of DNA synthesis. This allowed cells to proceed through S and G2-M phases during and after drug exposure, resulting in a doubling of cell number by 48 h after drug washout. As they attempted to progress through the cell cycle a second time, ganciclovir-treated cells accumulated in early S-phase and remained there until cell death, suggesting that ganciclovir incorporation in the DNA template was important for cytotoxicity. In contrast, strong inhibition of DNA synthesis by araTTP prevented cells from traversing the cell cycle for at least 12 h after drug washout, when the active metabolite was largely degraded araT-treated cells were unable to divide for at least 72 h after drug exposure, at which point the surviving cells displayed a normal cell cycle distribution pattern. Based on the results presented here, we propose a novel paradigm in which the ability of ganciclovir to incorporate into DNA without inhibiting progression through S-phase, combined with high cytotoxicity for incorporated ganciclovir monophosphate, produces multilog cytotoxicity.