The effect of penciclovir and acyclovir on the replication of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) strains was determined in MRC-5 cells infected with 0.01 pfu/cell and exposed to the drugs for 72 h to allow multiple cycles of replication. Penciclovir was significantly more active than acyclovir against three strains of HSV-1 and three strains of HSV-2 at 1 mg/L (P = 0.009), 3 mg/L (P < 0.001) and 10 mg/L (P = 0.001). Further comparisons between the compounds were made in MRC-5 cells infected with HSV-1 strain SC16 using four different antiviral assays namely, the 24 h virus yield reduction assay, plaque reduction assay, viral antigen inhibition assay, and a viral DNA inhibition assay, to determine the relative merits of each. Penciclovir and acyclovir shared similar activities in the plaque reduction assay (with 50% effective concentrations, EC50, being 0.8 and 0.6 mg/L, respectively) and in the viral antigen inhibition assay (EC50s. 0.6 and 0.7 mg/L, respectively). The EC50 of penciclovir in the 24 h viral DNA inhibition assay was 0.01 mg/L compared with 0.06 mg/L of acyclovir. In the 24 h virus yield reduction assay in which MRC-5 cells were infected with 0.3 pfu/cell, penciclovir was more active than acyclovir with 99% effective concentrations of 0.6 mg/L and 1.1 mg/L, respectively. The activity of penciclovir in the 24 h virus yield reduction and antigen inhibition assays was inversely related to the multiplicity of infection, whereas this had considerably less effect on the inhibition of viral DNA synthesis. These results suggest that famciclovir, which is the oral form of penciclovir, will be at least as effective as acyclovir in treating infections caused by HSV-1 and HSV-2.

BACKGROUNDAmerican Indians have excess risk of depression, which can contribute to cerebrovascular and cognitive disability, with effects on memory, processing speed, executive function, and visuospatial ability. However, studies examining depression and cognition in American Indians are limited; this study aims to report associations of depression with general cognition, verbal fluency and memory, and processing speed.DESIGNCohort study.SETTINGThe Cerebrovascular Disease and its Consequences in American Indians study was an ancillary examination of Strong Heart Study participants from 3 U.S. regions.PARTICIPANTSAll eligible were included in this analysis (N=818).MEASUREMENTSParticipants completed evaluations for depressive symptomology, cognition, and physical function—including Center for Epidemiologic Studies Depression (CESD), Modified Mini‐Mental State Examination (3MSE), Wechsler Adult Intelligence Scale‐Fourth Edition coding (WAIS), Controlled Oral Word Association (COWA), California Verbal and Learning Test, Halstead finger tapping, grip strength, and Short Physical Performance Battery (SPPB) tests. Linear mixed models were adjusted for site, age, sex, education, income, marital status, alcohol, smoking, diabetes, hypertension, obesity, cholesterol, stroke, infarct, and hemorrhage.RESULTSSymptoms of depression were common, with 20% (N=138) endorsing CES‐D scores of 16+. More depressive symptoms were associated with older age, female sex, lower education, lower income, non‐married status, not using alcohol, not smoking, hypertension, diabetes, and stroke. In adjusted analyses, processing speed (WAIS: β −0.13, 95%CI −0.25, −0.03), general cognition (3MSE: β −0.10, 95%CI −0.17, −0.03), verbal fluency (COWA: β −0.10, 95%CI −0.19, −0.01), and motor function (SPPB: β −0.05, 95%CI −0.07, −0.03) were significantly associated with more symptoms of depression.CONCLUSIONThese findings maybe informative for health disparities populations, especially those with depressive risk. Clinicians may require particular training in cultural humility. Future studies should validate use of the CES‐D scale in this population; longitudinal studies may focus on causal mechanisms and potential secondary prevention, such as social support. J Am Geriatr Soc 68:1739‐1747, 2020.

SummaryThe effect of penciclovir (BRL 39123) on the replication of varicella-zoster virus (VZV) in human embryonic lung fibroblasts (MRC-5 cells) was similar to aciclovir when the compounds were present continuously. However, when the compounds were withdrawn the antiviral activity of penciclovir was maintained more effectively than that of aciclovir. In the plaque reduction assay, median 50% effective concentrations (ECsos) were 3.8 I1g mr" for penciclovir and 4.2 I1g rnl" for aciclovir (n =29 clinical isolates). Similarly, penciclovir and aciclovir were equally effective in reducing the numbers of VZV-infected MRC-5 cells and in reducing VZV DNA synthesis within infected cells following continuous treatment. Within VZVinfected cells (S)-penciclovir-triphosphate was formed from penciclovir with >95% enantiomeric purity, and the concentration of penciclovir-triphosphate was 360-fold greater than aciclovir-triphosphate immediately after treatment. This phosphorylation ratio compensates for the lower affinity of VZV DNA polymerase for penciclovir-triphosphate compared with aciclovir-triphosphate (K;s =7.5 11M and 0.2 11M, respectively). When VZV-infected cultures were treated for 3 days, followed by withdrawal of the compound, inhibition of viral DNA synthesis by penciclovir was maintained for 24 h, whereas viral DNA synthesis resumed more readily after removal of aciclovir. Furthermore, following 8 h daily pulse treatment for 5 days, penciclovir was significantly more active than aciclovir in reducing VZV DNA synthesis (p =0.006, n =10 clinical isolates). The long intracellular half-life of penciclovir-triphosphate (9.1 h) compared with that of aciclovir-triphosphate (0.8 h)

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SummaryThe replication of herpes simplex virus type 1 (HSV-1) or HSV-2 in MRC-5 cells infected at 0.01 pfu ceni and treated continuously for 72 h, was inhibited more efficiently by penciclovir than aciclovir (p =0.0001).However, multiple cycles of replication were required in order to distinguish the compounds. Virus from cultures treated for 72 h with either compound, at 3 or 10 /1g mr", was resistant to penciclovir and aciclovir (50% effective concentrations> 10 /1g mr"), but infectivity titres of supernatants from these aciclovirtreated cultures were higher than for penciclovir. Increased production of resistant virus in aclclovlrtreated cultures may be the consequence of the less potent inhibition of virus replication by aciclovir. Penciclovir caused prolonged inhibition of HSV-1 and HSV-2 replication in three human cell lines infected at 1 pfu celr" following treatment for 18 h, whereas virus replication resumed rapidly after withdrawal of aclclovir. Neither compound showed prolonged activity after 18 h treatment, when the multiplicity of infection was reduced to 0.01 pfu ceir'. This surprising observation prompted experiments testing the effect of repeated pulse treatment in cultures infected at low multiplicity. Penciclovir inhibited HSV-1 replication significantly more effectively than aciclovir in MRC-5 cells infected at 10-4 pfu ceni and treated daily for 6 h (p < 0.001, n =5) but only a trend was observed for HSV-2 (p =0.06, n =6).