Long-term oral Acyclovir / Aciclovir therapy. Effect on recurrent infectious herpes simplex keratitis in patients with and without grafts.

PURPOSE: To evaluate the efficacy of long-term oral Acyclovir / Aciclovir therapy in reducing recurrences of dendritic or geographic herpes simplex keratitis (HSK). METHODS: Thirteen patients with a history of frequently recurring HSK were followed before (mean, 27 months) and during long-term systemic Acyclovir / Aciclovir, and eight were followed after the Acyclovir / Aciclovir was discontinued. RESULTS: Treatment ranged from 8.5 to 62 months (mean, 34 months). During treatment, the number of recurrences per month decreased from 0.15 to 0.03, and the average duration of relapses decreased from 12.6 to 7.8 days. Recurrences correlated with daily doses of oral Acyclovir / Aciclovir of 800 mg or less, intraocular surgery within 6 weeks of initiating treatment, and discontinuation of therapy against medical advice. CONCLUSION: The results of this small study appear to demonstrate the efficacy of long-term oral Acyclovir / Aciclovir in prophylaxis of recurrent epithelial herpes simplex infection: therapeutic doses of oral Acyclovir / Aciclovir reduce both the rate and duration of recurrences of infectious herpetic keratitis. A multicenter, double-masked, placebo-controlled study is indicated.

Pharmacokinetics of Acyclovir / Aciclovir in patients undergoing continuous venovenous hemodialysis.

The pharmacokinetics of Acyclovir / Aciclovir in three patients undergoing continuous venovenous hemodialysis was investigated. Acyclovir / Aciclovir was administered as an intravenous infusion over 1 hour at a dose of 5 mg/kg daily in one patient and 10 mg/kg every 48 hours in two patients. Samples from the arterial and venous blood lines and from ultrafiltrate were collected to calculate pharmacokinetic parameters, sieving coefficient and clearance of ultrafiltration. Plasma concentrations of Acyclovir / Aciclovir were assessed by high-performance liquid chromatography. Peak plasma concentrations were 9.3 mg/l for the patient receiving 5 mg/kg daily, 29.6 mg/l and 20.7 mg/l for the two patients with 10 mg/kg every 48 hours. The elimination half-life ranged from 8.8 to 11.2 hours and was approximately half those found in patients with renal impairment. The clearance by ultrafiltration was from 17.4 to 22.3 ml/minute and reached nearly 35% of the total clearance. The sieving coefficient ranged from 0.92 to 0.98 with an average rate of removal over the dosing interval ranging from 6.7 to 13.0 mg/hour. These data should be taken into account to optimize drug therapy in patients on continuous hemodialysis. Until formal guidelines are defined, Acyclovir / Aciclovir dosage should be adjusted according to monitoring of plasma drug concentrations.

Technique validation by liquid chromatography for the determination of Acyclovir / Aciclovir in plasma.

In this research project, a high-performance liquid chromatography (HPLC) method was developed for the determination of Acyclovir / Aciclovir (ACV) in plasma. The plasma samples, recharged with Acyclovir / Aciclovir and in presence of 5'-N-methylcarboxyamidoadenosine (MECA) as an internal standard, were purified using a solid-phase extraction technique with Waters Oasis HLB columns. The separation of the components from the extract was carried out in a LiChrospher 100 RP-18 column for further ultraviolet detection at a wavelength range of 250-260 nm. The mobile phase composition was 18% acetonitrile, sodium dodecylsulphate 5 mM and phosphate buffer at pH 2.6 with an analysis time of 13 min per sample. The average retention time for Acyclovir / Aciclovir was of 5.0 min and for the internal standard 11.2 min. The calibration curve was linear ranging between 0.05 and 1.80 microg/ml. The detection limit was 0.006 microg/ml with a quantification limit of 0.020 microg/ml. The ACV recuperation percentage for 250 microl of plasma was between 94.7 and 109.7% with a coefficient of variation not higher than 5.2%. This method was developed and validated for use in bioavailability and bioequivalence studies.

Bile salt-fatty acid mixed micelles as nasal absorption promoters. III. Effects on nasal transport and enzymatic degradation of Acyclovir / Aciclovir prodrugs.

The absorption enhancement and presystemic degradation kinetics of a homologous series of Acyclovir / Aciclovir 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 / Aciclovir 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 / Aciclovir 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 / Aciclovir prodrugs were also determined.(ABSTRACT TRUNCATED AT 250 WORDS)