Replication 386 INDEX

HIV infection occurs through three primary modes of transmission sexual, parenteral, and perinatal. The most common method for transmission is receptive anal and vaginal intercourse, with the probability of transmission up to 3% per sexual contact for the former, and up to 0.2% per sexual contact for the latter. The probability of transmission increases when the index partner has a high level of viral replication (which occurs at the very beginning of infection or late in disease), or when the uninfected partner has ulcerative disease, compromised mucosal surfaces, or (in the case of men) has not been circumcised. 

Vertzoni et al. (30) recently clarified the applicability of the similarity factor, the difference factor, and the Rescigno index in the comparison of cumulative data sets. Although all these indices should be used with caution (because inclusion of too many data points in the plateau region will lead to the outcome that the profiles are more similar and because the cutoff time per percentage dissolved is empirically chosen and not based on theory), all can be useful for comparing two cumulative data sets. When the measurement error is low, i.e., the data have low variability, mean profiles can be used and any one of these indices could be used. Selection depends on the nature of the difference one wishes to estimate and the existence of a reference data set. When data are more variable, index evaluation must be done on a confidence interval basis and selection of the appropriate index, depends on the number of the replications per data set in addition to the type of difference one wishes to estimate. When a large number of replications per data set are available (e.g., 12), construction of nonparametric or bootstrap confidence intervals of the similarity factor appears to be the most reliable of the three methods, provided that the plateau level is 100. With a restricted number of replications per data set (e.g., three), any of the three indices can be used, provided either non-parametric or bootstrap confidence intervals are determined (30). 

Table 2 Index Values from the Simulated Non-cumulative Data Sets with No Built-in Error, and 50th (5th— 95th) Percentiles of Each of the 1000-Sized Bootstrap Index Sample Constructed from 3-fold, 6-fold, and 12-fold Replicated Data Sets with Built-in Error... 

Direct isolation of sufficient quantities of each metabolite for structural characterization, assay validation and pharmacological or toxicological testing from in vivo studies using biological specimens is, therefore, often impossible, particularly from dmgs with a low therapeutic index. Furthermore, many metabolites have structural modifications which are difficult to replicate by traditional chemical methods. A number of synthetic steps may be required to prepare such metabolites from the API, or, in the worst case, a completely new synthetic route may need to be developed. 

In short-term renal toxicity studies in rats gavage administration of 1,1,2,2-tetra-chloroethane caused renal toxicity as evidenced by an increased renal tubule cell labeling index, indicating replicative DNA synthesis. In 2-year studies 1,1,2,2-tetrachloroethane administered by gavage produced an increased incidence of hepatocellular carcinomas in mice but not in rats. In one epidemiological study of exposed army workers there was a slight increase in deaths due to genital cancer and leukemia. Exposure levels were not available,... 

Extensive destruction of the olfactory epithelium was observed in male Fischer 344 rats exposed to 200 ppm [780 mg/m ] methyl bromide for 6 h per day for five days. By day 3, despite continued exposure, there was replacement of the olfactory epithelium by a squamous-cell layer, followed by progressive reorganization toward the normal architecture, and by week 10,75-80% of the epithelium appeared histologically normal. Olfactory epithelial-cell replication was maximal on day 3 of exposure, with a labelling index of 14.7% compared with 0.7% in the controls (Hurtt et al., 1988). Degeneration and subsequent regeneration were also observed in an inhalation experiment w ith Fischer 344 rats exposed to 175 ppm [680 mg/m ] 6 h twice, separated by a 28-day interval (Bolon et al., 1991). 

Concentration that inhibited cell growth by 50%. b Concentration that inhibited viral replication by 50%. c Therapeutic index IC50 divided by EC50. 

Two saponins from soybean seeds having soyasapogenol as aglycone were shown to have a partial inhibitory effect on HIV-induced cytopathology in infected human MT-2 lymphocytes cultures [158], The major constituent of group of B saponins from soybean seeds completely inhibited HIV-induced cytophatic effects and virus-specific antigen expression 6 days after infection at concentration > 0.25 mg/ml. Saponins isolated from soybean seeds inhibited HIV-1 replication in MT-4 cells at 0.5 [tg/ml (Nakamura et al. 1992) [159]. These saponins had a narrow therapeutic index and did not inhibit HIV-1 RT. One of them was found to inhibit HIV-induced cell fusion in MOLT-4 cells. 

Measurement of the Spectral Intensity For measurement, we use the residual 360 nm peak as internal reference (23). The fluorescence intensity is recorded in the standard method at 430 nm. Fluorescence index is defined by us as the ratio 1430/1350 This is measured at every sampling period for both the blank, the control without antioxidant, and the antioxidant-treated sample. Relative mean deviation of replicate measurements (repositioning the plate) is +5%. 

Betulinic acid and platanic acid are triterpenoids isolated from Syzygium claviflorum. They exhibit inhibitory activity against HIV-1 replication in H9 lymphocyte cells at an IC50 of 1.4 and 6.5 pM, respectively (selectivity index 9.3 and 14, respectively). Hydrogenation of betulinic acid... 

Variables ai (lj and x are actual effects of i rows, j columns and the k factor level. One can notice that the k index is bracketed to indicate that in the design of Latin squares there are no m results, as is the case with a three-factorial design with one design-point replication. Design of Latin squares actually has m2 observations or data. 

Fluoxetine is a selective serotonin-reuptake inhibitor (SSRI) that produces a net increase in (post-synaptic motor neuron) serotonin delivery after 4-6 weeks of use. A double-blind, randomized cross-over trial compared fluoxetine to the tricyclic antidepressant agent protriptyline and placebo in 12 patients with sleep-disordered breathing [52], The group apnea-hypopnea index (AHI) improved with fluoxetine compared to placebo, but there was great variability of response and other measures of disordered sleep did not change. These potentially beneficial results in a small number of patients need to be replicated in well-designed larger studies to support a useful role in clinical practice. 

The index does not take into account test variability (i.e., coefficient of variation of response for a set of laboratory replicates for each sampling station). 

The dibenzylbutyrolactone lignan matairesinol was also found to be an anti-HIV agent [110], although the sample used in this bioassay was not isolated from a Taxus species. Another dibenzylbutyrolactone lignan, arctigenin, as well as its unsubstituted benzyl derivative exhibited anti-HIV replication activity, with EC50 values of 0.16 and 22 ig/mL and therapeutic index values of 5 and 9.1, respectively [111]. 

A second class of antiviral compounds has been developed to inhibit viral replication by acting on the RNA polymerase (Fig. 17.3b). T-705 (favipiravir, 3) undergoes ribosylation and then phosphorylation and is believed to function similarly to a nucleobase in viral RNA replication [35,45], T-705 has been demonstrated to inhibit viral replication of influenza A, B, and C viruses, and recent studies have shown encouraging results toward it becoming a potential drug candidate [45,46], Compared to the most familiar polymerase inhibitor ribavirin (4), T-705 has a more favorable therapeutic index in preclinical test of toxicity [34, 35],... 

The function in Example 4.4 can be used to autoscale a data matrix. The function determines the size of the argument, its mean vector, and its standard deviation vector. On the last fine, a MATLAB programming trick is used to extend the mean vector and standard deviation vector into matrices having the same number of rows as the original argument prior to subtraction and division. The expression ones < r, i) creates an r x 1 column vector of ones. When used as an index in the statement mn (ones(r,1), ), it instructs MATLAB to replicate the mean vector r times to give a matrix having the dimensions r x c. 

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