Therapeutic ratios

Replacement of the phenyl group at the 2 position by diphe-nylacetyl affords an anticoagulant with long duration of action and improved therapeutic ratio. Condensation of dimethyl phthal-ate with 1,1-diphenylacetone (17) in the presence of base affords phenindandione (18). ... 

A variant on this structure, dioxyline, has much the same activity as the natural product but shows a better therapeutic ratio. Reduction of the oxime (113) from 3,4-dimethoxyphenyl-acetone (112) affords the veratrylamine homolog bearing a methyl group on the amine carbon atom (114). Acylation of this with 4-ethoxy-3-methoxyphenyl acetyl chloride gives the corresponding amide (115). Cyclization by means of phosphorus oxychloride followed by dehydrogenation over palladium yields dioxyline (116). ... 

The therapeutic ratio of antineoplastic agents, which is defined by the dose necessary to cause a significant anticancer effect divided by the dose effecting significant side effects, is generally low (near to one). 

Therapeutic ratio, so that the concentration of the compound to elicit its therapeutic effect is much lower than the concentration that would cause untoward effects... 

A relatively wide range of blood concentrations is therapeutically acceptable. The drug does not have a low therapeutic ratio. 

These statistics tends to belie the notion that children and the elderly, although somewhat more vulnerable, are extremely more likely to succumb to overdose. None of these data clearly establish the LD50 however, which is required to estimate the therapeutic ratio (LD50/ID50) for atropine. This ratio is an important key to making reasonable estimates of lethality for the other belladonnoids, since there are no BZ deaths (for example) from known dosage on which to base such estimates. 

Of course, none of these data precisely establish the LD50, which is needed to estimate the therapeutic ratio (LD50/ID50). Nevertheless, extrapolation of the approximate therapeutic ratio for atropine (while also taking into account that lethality among the glycolates is proportional to their peripheral potency) provides the most feasible way to estimate the LD50 for the other belladonnoids (none of which have been known to have caused death in humans). 

This establishes, by analogy, a high therapeutic ratio for such compounds as 3167, 3443, 3580 as well as the less thoroughly studied 302282 and 226086. A high relative central to peripheral potency, combined with high absolute central potency produces a belladonnoid that has both low dose requirements and a high safety margin (therapeutic index). These compounds, consequently, would seem to be both safer and more effective than BZ. 

Hunt et al. [6] demonstrated that the DTI is also equivalent to the ratio of the therapeutic index (abbreviated to TI in Hunt et al. s paper in this chapter TI is defined differently, see Section 13.4.3) of the drug-carrier conjugate and that of the free drug. The therapeutic index (also called the therapeutic ratio) is a statistical measure defined as the ratio of the median toxic dose to the median effective dose [22]. 

MULTISUBSTRATE MECHANISMS THERAPEUTIC RATIO THERMAL EQUILIBRATION THERMAL LENSING Thermal noise,... 

The dose of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios, or being given to patients with hepatic impairment, may require adjustment to maintain optimal therapeutic blood levels when starting or stopping concomitant therapy with ticlopidine. 

The concept of the therapeutic ratio is key here as it implies that the effect of the combination therapy is greater in the tumor than in the relevant normal tissues within the treated radiation volume. The therapeutic ratio is often described in a mathematical formulation as the ratio of dose enhancement factors in the tumor divided by that in the normal tissues. The following are clear examples of clinical situations where the use of concurrent therapy has been found to be associated with an improvement in the therapeutic ratio. 

Mason KA, Kishi K, Hunter N, et al. Effect of docetaxel on the therapeutic ratio of fractionated radiotherapy in vivo. Clin Cancer Res 1999 5(12) 4191 1198. 

Kirichenko AV, Travis EL, Rich TA. Radiation enhancement by 9-aminocamptothecin. Evidence for improved therapeutic ratio with a multiple dose schedule. Ann NY Acad Sci 1996 803 312-314. 

In order to maximize the therapeutic ratio between efficacy and toxicity, a balance must exist between radiation dose and the volume of the radiation port. The volume of the radiation port affects the amount of radiation that can be given. In regards to toxicity of radiation, total radiation dose is inversely related to the volume of the radiation port... 

Selective COX-2 inhibitors are currently being investigated in cancer patients in phase I and early phase II clinical trials. The currently available data would suggest that specific inhibitors of COX-2 have the potential to increase the therapeutic ratio of radiotherapy in tumors that express COX-2, and that clinical investigation of this interaction is warranted. 

Withering s discovery of the clinical use of digitalis was important, but it may well be that his contribution to the methodology of pharmacology and therapeutics was of even greater importance. His rejection of polypharmacy, his attention to pharmaceutical product quality and to the standardization of his remedy, and his development of the technique of dose-titration enabling a drug with the narrowest of therapeutic ratios to be used safely - were recorded in a way that seems as fresh today as it ever was. These aspects of his work, the careful and detailed nature of his clinical observations, and the aphoristic nature of his splendid Inferences continue to excite one s admiration today (see Mann, 1985). 

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