The single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride were compared in a randomized, two-period, crossover study involving six young (<35 years) and six elderly (.60 years) adults. Subjects ingested single 200-mg oral doses after an overnight fast, and serial plasma (0 to 96 h), nasal mucus (0 to 8 h), and urine (0 to 24 h) samples were collected for assay of drug concentration by electron capture gas chromatography. For both groups combined, rimantadine differed significantly from amantadine in peak plasma concentration (mean standard deviation, 0.25 ± 0.06 versus 0.65 0.22 ,ug/ml), plasma elimination half-life (36.5 15 versus 16.7 ± 7.7 h), and percentage of administered dose excreted unchanged in urine (0.6 0.8 versus 45.7 + 15.7%). No significant age-related differences were noted for rimantadine. Urinary excretion (0 to 24 h) of rimantadine and its hydroxylated metabolites averaged 19% of the administered dose. The maximum nasal mucus drug concentration was similar for both drugs (0.42 + 0.25 versus 0.45 0.32 ,ug/g), and the ratio of maximum nasal mucus to plasma concentration was over twofold higher after rimantadine than after amantadine. These findings may in part explain the clinical effectiveness of rimantadine in influenza A virus infections at dosages that have lower toxicity than those of amantadine.The adamantane compounds, amantadine hydrochloride and rimantadine hydrochloride, have well-documented prophylactic and therapeutic efficacy in influenza A virus infections (5, 21). Limited in vitro and animal model results suggest that rimantadine has greater influenza A virusinhibitory activity than amantadine (7,15,19). More importantly, clinical studies have found that at equivalent oral dosages of 200 mg (5) or 300 mg (8) per day rimantadine is associated with significantly fewer central nervous system side effects than amantadine. The differences in side effect rates observed between the two drugs appear to be related to differences in plasma concentrations (8). Whereas amantadine pharmacokinetics have received extensive study (1-4, 9, 17), the pharmacokinetics of oral rimantadine have not been delineated. Limited results in healthy adults indicate that rimantadine is associated with significantly lower plasma concentrations after single or multiple doses (8) and has a longer plasma half-life and lower urinary excretion than amantadine (20). In addition, the pharmacokinetics of these drugs have not been defined in the elderly, one of the target populations for the prevention of influenza A virus infections.The current study was conducted to determine the comparative single-dose pharmacokinetics of amantadine and rimantadine in both young and elderly adults. This study also incorported collection of nasal mucus samples to determine concentrations of these drugs in respiratory secretions after systemic administration.MATERIALS AND METHODS Study design. This study was a randomized, open-label, two-treatment, crossover study in which rimantadine and amantadine were ...

In a double-blind, placebo-controlied study, the comparative toxicities and blood concentrations of amantadine hydrochloride and rimantadine hydrochloride were determined. Healthy, working adults ingested either 200 (n = 52) or 300 mg (n = 1%) per day in divided doses for 4.5 days. Mean plasma drug concentrations at 4 h after the first dose were lower in rimantadine recipients given 100-(140 versus 300 ng/ml for rimantadine and amantadine, respectively; P < 10-5) or 200-mg doses (310 versus 633 ng/ml; P < 10-5). The plasma drug concentrations after the first dose correlated significantly with total symptom sources for both amantadine and rimantadine, but the plasma levels of toxic and nontoxic subjects overlapped extensively. At 300-mg/day dosage amantadine was associated more often with adverse central nervous system symptoms (33% of amantadine versus 9% of rimantadine recipients; P < 0.001) and sleep disturbance (39 versus 13%; P < 0.001), but not gastrointestinal symptoms (19.5 versus 16.0o). However, no differences between the drugs were noted in symptom frequency or scores in volunteers with similar plasma concentrations. Amantadine and rimantadine differ in their pharmacokinetics but not in their potential for side effects at comparable plasma concentrations.Clinical trials have documented that amantadine hydrochloride (8,12,16,20,28) and its analog rimantadine hydrochloride (6,12,23,28,29) are effective drugs for the prophylaxis and treatment of influenza A virus infection. However, widespread use of amantadine has been limited in part by concern about its side effects.Most studies of amantadine prophylaxis have documented minimal toxicity at a dosage of 200

Investigations over the last decade have established the essential role of growth factors and their receptors during angiogenesis. The biological significance of VEGF, EGF, and bFGF is mediated by their receptors, which belong to the family of tyrosine kinase receptors: Flt-1 (VEGFR-1), KDR (VEGFR-2), EGFR, FGFR-1, FGFR-2, FGFR-3, and FGFR-4. Deeper understanding of the mechanism of activation of these growth factor receptors has allowed the development of a new pharmacological strategy aimed at controlling cancer cell proliferation. The results of a large body of preclinical as well as early clinical studies conducted suggest that targeting the growth factor receptors could represent a significant contribution to cancer therapy.

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