Therapeutic efficacy/potency

Serendipity has played a major role in the discovery of most classes of psychotropic drugs. For example, the observation that the first antidepressants, the tricyclic antidepressants and the monoamine oxidase inhibitors, impeded the reuptake of biogenic amines into brain slices, or inhibited their metabolism, following their acute administration to rats, provided the experimenter with a mechanism that could be easily investigated in vitro. Such methods led to the development of numerous antidepressants that differed in their potency, and to some extent in their side effects (for example, the selective serotonin reuptake inhibitors) but did little to further the development of novel antidepressants showing greater therapeutic efficacy. The accidental discovery of atypical antidepressants such as mianserin led to the broadening of the basis of the animal models... 

At times, a drug that affects more than one target simultaneously may be preferable for specific indications because of desired consequences, such as enhanced potency, wider therapeutic efficacy (e.g., greater spectrum of activity in a heterogeneous condition such as major depression), faster onset of desired activity, or better tolerability. There are four goals of new drug development ... 

To ensure lot-to-lot consistency, standardization of extracts often relies on constituents as biomarkers for plant identity and potency. SJW Hypericum perforatum), a perennial shrub traditionally used as a mood enhancer and mild antidepressant, has been tested in dozens of clinical trials, with mixed results for efficacy. Some of its purported bioactive constituents include naphthodianthrones, including hypericin flavonoids phloroglucinols, including hyperforin and essential oils. For many years, hypericin was presumed to be the active component. As a result most extracts were standardized based on hypericin concentration. Recent data, however, support other components such as hyperforin and the flavanoids, that may also contribute to the therapeutic efficacy of the SJW extracts (33-35). Because these secondary components were previously unaccounted for in the standardization of the former clinical test articles, and because these constituents are chemically unrelated to and their content within the plant varies independently of hypericin, it has been argued that the potency of these constituents in any particular batch was unlikely to be similar to that of other batches. This variability between batches could explain the observed differences in the clinical trial results (36). 

Oximes bind to AChE as reversible inhibitors and form complexes with AChE either at the acylation (catalytic) site, at the allosteric site, or at both sites of the enzyme and protect AChE from phosphorylation. When the reversible inhibitor binds to the catalytic site, the protection is due to direct competition between OP and reversible inhibitor. Binding of a reversible inhibitor to the allosteric site induces indirect protection of the active site. Differences in the mechanisms of enzyme reactivation and protection demonstrate how stereochemical arrangements of oximes can play a role in the potency of their therapeutic efficacy. Direct pharmacological effects, such as direct reaction with OPs (Van Helden et al., 1996), anticholinergic and sympathomimetic effects may also be relevant for the interpretation of antidotal potency of oximes. 

Quantitative aspects Dose response, Potency, Therapeutic efficacy.Tolerance... 

Since the potency (therapeutic efficacy in relation to weight) of antipsychotic agents varies markedly between compounds, it is useful to think of the effective antipsychotic dose of classical agents in terms of chlorpromazine equivalents (see Table 19.5). For example, haloperidol has a relatively high anh-psychotic potency, such that 2-3 mg is equivalent to chlorpromazine 100 mg, whereas sulpiride 200 mg (low potency) is required for the same antipsychotic effect. 

There was still no requirement to prove product efficacy. But in 1941, with most of the world at war, an often overlooked piece of US legislation was passed. The FD C Act was amended, to reflect an FDA proposal. Henceforth, FDA was empowered to certify the potency of insulin. This required a bioassay, and for the first time FDA was able to regulate pharmacodynamics. It was a short step to therapeutic efficacy. 

Dothiepin (Dosulepin) is the thio isostere of doxepin and is marketed in Europe as its single E-geometric isomer (Fig. 21.1 7), in contrast to the active Z-geometric isomer for doxepin. Its antidepressant activity is mediated by inhibition of both the NET and SERT, with preferential affinity for SERT (65). It exhibits greater overall in vitro affinity for NET and SERT than its oxygen isostere doxepin, consistent with its greater potency. Its overall therapeutic efficacy is similar to that of amitriptyline. 

In the formulation of any pharmaceutical product, it is imperative to ensure that the ingredients used are compatible with one another. Incompatibilities can occur between drug and excipient as well as between the excipients themselves. Incompatibilities may be manifested through many modes, such as acid-base interaction and complex formation, resulting in lower potency and/or stability and eventually poor therapeutic efficacy of the product. It is therefore essential to avoid incompatibilities and this is achieved by carrying out studies to detect potential interactions between the components used in the formulation. 

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

Influencing the efficacy or potency of chemicals is a strategy used by the pharmaceutical industry as part of the drug discovery process that can be incorporated into designing safer industrial chemicals. Efficacy is the maximal effect, either therapeutic or toxic, that a chemical can achieve. Potency is a measure of the amount of a substance that is needed to attain a given response level. Opioid analgesics are examples of where structural modifications have been used to establish a relationship between structure and activity. ... 

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