RESUMO
Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (approximately 12.5 mg/kg of body weight [BW] for children weighing < 40 kg and 500 mg for children weighing > or = 40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to < 6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW(0.696). An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose.
Assuntos
2-Aminopurina/análogos & derivados , Antivirais , Varicela/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 3/efeitos dos fármacos , Simplexvirus/efeitos dos fármacos , 2-Aminopurina/administração & dosagem , 2-Aminopurina/efeitos adversos , 2-Aminopurina/farmacocinética , Aciclovir/administração & dosagem , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Varicela/virologia , Criança , Pré-Escolar , Esquema de Medicação , Quimioterapia Combinada , Famciclovir , Feminino , Herpes Simples/virologia , Humanos , Lactente , Masculino , Resultado do TratamentoRESUMO
A whole plant chloroform-methanol extract of the orchid Epidendrum rigidum inhibited radicle growth of Amaranthus hypochondriacus seedlings (IC50 = 300 microg/mL). Bioassay-guided fractionation furnished four phytotoxins, namely, gigantol (1), batatasin III (2), 2,3-dimethoxy-9,10-dihydrophenathrene-4,7-diol (9), and 3,4,9-trimethoxyphenanthrene-2,5-diol (11), along with the known flavonoids apigenin, vitexin, and isovetin and the triterterpenoids 24,24-dimethyl-9,19-cyclolanostane-25-en-3beta-ol (14) and 24-methyl-9,19-cyclolanostane-25-en-3beta-ol (15). Stilbenoids 1, 2, 9, and 11 inhibited radicle growth of A. hypochondriacus with IC50 values of 0.65, 0.1, 0.12, and 5.9 microM, respectively. Foliar application of gigantol (1) at 1 microM to 4 week old seedlings of A. hypochondriacus reduced shoot elongation by 69% and fresh weight accumulation by 54%. Bibenzyls 1 and 2, as well as synthetic analogues 4'-hydroxy-3,3',5-trimethoxybibenzyl (3), 3,3',4',5-tetramethoxybibenzyl (4), 3,4'-dihydroxy-5-methoxybibenzyl (5), 3'-O-methylbatatasin III (6), 3,3',5-trihydroxybibenzyl (7), and 3,4',5-trihydroxybibenzyl (8), were tested for phytotoxicity in axenic cultures of the small aquatic plant Lemna pausicostata. All bibenzyls derivatives except 7 and 8 inhibited growth and increased cellular leakage with IC50 values of 89.9-180 and 89.9-166 microM, respectively. The natural and synthetic bibenzyls showed marginal cytotoxicity on animal cells. The results suggest that orchid bibenzyls may be good lead compounds for the development of novel herbicidal agents.