Enferm Infecc Microbiol Clin. 2000 Dec;18(10):493-5.
[Varicella pneumonia in the adult: study of 22 cases]

[Article in Spanish]

de la Pena L, Izaguirre D, Aguirrebengoa K, Grande C, Montejo M.

Unidad de Enfermedades Infecciosas, Hospital de Cruces, Bilbao.

BACKGROUND: Retrospective study of the varicella pneumonia in adults with clinical, therapeutic and evolutive features in 22 patients in the last 5 years. MATERIAL AND METHODS: The diagnosis was established by clinical and radiologic criteria in the course of varicella infection. The antecedents of pregnancy, smoking habit, previous contact with patients with varicella and underlying disease were evaluated. RESULTS: Twenty-two patients (14 males and 8 women: mean age 31 years. range: 22-40) were included in the study. None of them were immunocompromised, 16 (72.7%) have had previous contact with varicella patients. 19 (86.3%) were heavy smokers and none of the female patients was pregnant. All patients had fever and exanthem, cough had 20 (90.9%) dyspnea 16 (72.7%), chest pain 9 (40.9%) and hemoptysis 5 (22.7%). Only two patients showed pO2 < 60 mmHg. Chest X-ray revealed an interstitial pattern in 14 cases (63.3%), and micronodular in 8 (36.3%). All patients received treatment with intravenous acyclovir. Three patients (13.6%) were admitted to the Intensive Care Unit due to respiratory insufficiency, needing mechanical ventilation one of them (4.5%). Another three developed failure renal reversible associated with acyclovir. All patients had a favourable clinical course. CONCLUSIONS: We believe, that early, aggressive use of intravenous acyclovir in adult varicella pneumonia may be lifesaving, preventing progressive respiratory failure and reducing the high mortality rate of the disease. Therapy with corticosteroids should be considered in addition to antiviral therapy in patients with severe varicella pneumonia. While oral acyclovir chemoprophylaxis is probably beneficial in populations with chicken pox.

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ucsd.edu

Acyclovir (ACV) triphosphate and azidothymidine (AZT) triphosphate inhibit the DNA polymerase of human hepatitis B virus (HBV) by 50% at submicromolar concentrations, but no effects of ACV or AZT treatment have been noted on the clinical manifestations of hepatitis B. We synthesized 1-O-octadecyl-sn-glycero-3-phospho-acyclovir (ODG-P-ACV), 1-O-hexadecylpropanediol-3-phospho-acyclovir (HDP-P-ACV), and 1-O-octadecyl-sn-glycero-3-phospho-azidothymidine (ODG-P-AZT), and evaluated their antiviral activity in human hepatoma cells that constitutively produce HBV (2.2.15 cells). ACV and AZT up to 100 microM caused only slight inhibition of HBV replication in 2.2.15 cells. However, HDP-P-ACV and ODG-P-ACV inhibited viral replication by 50% at 0.5 and 6.8 microM, respectively. ODG-P-AZT also showed increased antiviral activity, with a 50% reduction in HBV replication at 2.1 microM. Based on the EC50, HDP-P-ACV, ODG-P-ACV, and ODG-P-AZT were > 200, > 14.7, and > 48 times more active than their free nucleosides in reducing HBV replication in 2.2.15 cells. To evaluate the biochemical basis for the increased antiviral activity, we studied the uptake and metabolism of 1-O-octadecyl-sn-glycero-3-phospho-[3H]acyclovir (ODG-P-[3H]ACV) in HepG2 cells. Cellular uptake of ODG-P-[3H]ACV was found to be substantially greater than that of [3H]ACV, and cellular levels of ACV-mono-, -di-, and -triphosphate were much higher with ODG-P-ACV. ODG-P-[3H]ACV was well absorbed orally. Based on urinary recovery of tritium after oral or parenteral administration of the radiolabeled compounds, oral absorption of ODG-P-ACV in mice was 100% versus 37% for ACV. ODG-P-ACV plasma area under the curve was more than 7-fold greater than that of ACV. Lipid prodrugs of this type may be useful orally in treating viral diseases.

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J Pharm Pharmacol. 1997 Aug;49(8):737-42.
Bioadhesive microspheres for ophthalmic administration of acyclovir.

Genta I, Conti B, Perugini P, Pavanetto F, Spadaro A, Puglisi G.

Department of Pharmaceutical Chemistry, University of Pavia, Italy.

The bioavailability of acyclovir to the ophthalmic epithelium is low and when the drug is administered in ophthalmic ointment it must be applied every four hours. An emulsification technique has been used to prepare acyclovir-loaded chitosan microspheres with the aim of promoting the prolonged release of drug and increasing its ocular bioavailability. The microparticulate drug-delivery systems obtained have been characterized for their morphology and physicochemical characteristics by in-vitro dissolution tests and in-vivo ocular administration to rabbits. The results show that the microspheres obtained are always quite small--the diameters of 90% of the particles are < or = 25 microns (i.e. d 90% never exceeds 25 microns) and physicochemical characterization shows that the drug is homogeneously dispersed in an amorphous state inside the microspheres. The in-vitro dissolution profile of acyclovir from chitosan microspheres is slower than that for the raw drug. Results from in-vivo ocular administration of acyclovir-loaded microspheres to the rabbit eye show prolonged high concentrations of acyclovir and increased AUC values. The microparticulate drug-carrier seems a promising means of topical administration of acyclovir to the eye.

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Am J Obstet Gynecol. 1998 Aug;179(2):527-32.
Prevention of herpes simplex virus infection and latency by prophylactic treatment with acyclovir in a weanling mouse model.

Dobson AT, Little BB, Scott LL.

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, USA.

OBJECTIVE: Acyclovir is an antiviral agent that inhibits acute herpes simplex virus replication and decreases the frequency of reactivation, but it is not currently used to prevent primary disease or the establishment of latency. The purpose of this study was to reexamine the efficacy of acyclovir in preventing acute and latent herpes simplex virus infection. STUDY DESIGN: Mice were infected by footpad inoculation with 2 viral recombinants that express beta-galactosidase. Half of each group was treated prophylactically with intraperitoneal acyclovir and then given acyclovir in the drinking water. Four days after infection, the dorsal root ganglia were removed, fixed, and stained, and the number of cells expressing beta-galactosidase were counted. RESULTS: Compared with placebo, prophylactic acyclovir completely inhibited acute viral replication as evidenced by the absence of beta-galactosidase activity (P < .001) and significantly decreased the number of neurons harboring latent infection (P = .01). CONCLUSION: Acyclovir prophylaxis prevented acute and reduced latent ganglionic infection with herpes simplex virus in a weanling mouse model.

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Pharm Res. 1998 Sep;15(9):1382-6.
Cellular uptake mechanism of amino acid ester prodrugs in Caco-2/hPEPT1 cells overexpressing a human peptide transporter.

Han HK, Oh DM, Amidon GL.

College of Pharmacy, The University of Michigan, Ann Arbor 48109-1065, USA.

PURPOSE: This study characterized the cellular uptake mechanism and hydrolysis of the amino acid ester prodrugs of nucleoside antiviral drugs in the transiently transfected Caco-2 cells overexpressing a human intestinal peptide transporter, hPEPT1 (Caco-2/hPEPT1 cells). METHODS: Amino acid ester prodrugs of acyclovir and AZT were synthesized and their apical membrane permeability and hydrolysis were evaluated in Caco-2/hPEPT1 cells. The cellular uptake mechanism of prodrugs was investigated through the competitive inhibition study in Caco-2/hPEPT1 cells. RESULTS: L-Valyl ester of acyclovir (L-Val-ACV) was approximately ten fold more permeable across the apical membrane than acyclovir and four times more permeable than D-valyl ester of acyclovir (D-Val-ACV). Correspondingly, L-valyl ester of AZT (L- Val-AZT) exhibited three fold higher cellular uptake than AZT. Therefore, amino acid ester prodrugs significantly increased the cellular uptake of the parent drugs and exhibited the D,L-stereoselectivity. Furthermore, prodrugs were rapidly hydrolyzed to the parent drugs by the intracellular hydrolysis, following the apical membrane transport. In the inhibition studies, cephalexin and small dipeptides strongly inhibited the cellular uptake of L-Val-ACV while L-valine had no effect, indicating that the peptide transporter is primarily responsible for the apical membrane transport of L-Val-ACV. In addition, the cellular uptake of L-Val-ACV was five times higher in Caco-2/hPEPT1 cells than the uptake in the untransfected Caco-2 cells, implying the cellular uptake of L-Val-ACV was related to the enhancement of the peptide transport activity in Caco-2/hPEPT1 cells. CONCLUSIONS: Caco-2/hPEPT1 system is an efficient in vitro model for the uptake study of peptidyl derivatives. Amino acid ester prodrugs significantly improved the cellular uptake of the parent drugs via peptide transport mechanism and were rapidly converted to the active parent drugs by the intracellular hydrolysis.

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