Therapeutic efficacy

Therapeutic efficacy Therapeutic efficacy of a dosage regimen takes several weeks to assess. 

The future of drug research is at stake, as stated in Molecular Medicine Today, June 1999, Disease models will not only be of educational value but will also stimulate the use and development of models that are truly relevant to human disease, which will eventually catalyze the development of safe and efficacious therapeutics for human use. ... 

Can this type of cooperative-based design lead to a better exploitation of genomic information to yield safer and more efficacious therapeutic agents ... 

Cardiac safety index (CSI) What is the ratio of the exposure (dose or concentration) where a signal is first apparent (lowest effect level, LOEL), compared with a projection or measured efficacious unbound plasma concentration (ED90, EC90) associated with an efficacious therapeutic dose Although ability to extrapolate nonclinical effects to humans is imprecise, a large CSI may provide a basis for reducing concern whereas a CSI <10 may increase concern about a particular... 

Clinically Efficacy. It is evident from the mechanism of action of antihistamines and the etiology of allergic diseases that antihistamines in no sense achieve a cure of the patient s allergy. After the adrninistration of a therapeutic dose, a temporal blockade of the effects of histamine is obtained. Whereas classical antihistamines needed at least twice daily adrninistration, for most of the more recently introduced agents adrninistration once daily is sufficient. 

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

The anainoacridines, tacrine (19) and its 1-hydroxy metaboUte, velnacrine (20), are reversible inhibitors of AChE. Tacrine was synthesi2ed in the 1940s and has been used clinically for the treatment of myasthenia gravis and tardive dyskinesia (115). Placebo-controUed studies have indicated modest efficacy of tacrine to treat AD dementia (122,123) and in 1993 the dmg was recommended for approval by the PDA under the trade name Cognex. Tacrine (19) has been shown to interact with sites other than AChE, such as potassium channels (124) and muscarinic receptors. However, these interactions are comparatively weak and are not thought to contribute to the biological activity of the dmg at therapeutic levels (115). 

In 1962, amendments to the U.S. Federal Food, Dmg and Cosmetic Act (Kefauver-Harris amendments) promulgated regulations concerning the requirements for premarketing approval by the FDA. This legislation estabUshed requirements of proof of both safety and therapeutic efficacy and strict control of human clinical testing, for example, which have extended the time and cost to market a new dmg. Thus, whereas approximately 40 new dmgs were marketed annually from 1948 to 1962, this number had fallen to 12 by 1966. 

Phase II. Initial clinical studies for therapeutic safety and efficacy are performed in volunteer patients who are suffering from the disease for which the dmg has therapeutic promise. Recognition of toxic symptoms and side effects are vital at this point because these may occur here, even when not observed in animal studies or in Phase I. 

In 1966 the PDA utilized the services of the National Academy of Sciences—National Research Council (NAS—NRC) to estabhsh the relative therapeutic efficacies of prescription dmgs marketed between 1938 and 1962. Those products that were found to meet safety and efficacy requirements were allowed to stay on the market. Suitable changes were required for other products for compliance, ie, formulation or label changes, additional data... 

During the preformulation stage, the chemical and physical properties of the dmg moiety are studied exhaustively to ensure stabdity, safety, bioavadabdity, and therapeutic efficacy. Tablets are produced directly by compression of powder blends or granulations, which include a small percentage of fine, particle-sized powders. 

The therapeutic efficacy of a dmg is generally measured in terms of ED q or ID q which represent the concentration of dmg which produces 50% of the maximum effect or 50% of maximum inhibition. LD q represents the concentration of dmg that produces 50% fataUties in test animals. The therapeutic index is the ratio of the ED q versus LD q. Detailed descriptions of the terminology and fundamental principles of pharmacology are available (32) (see Pharmacodynamics). 

Common side effects of theophylline therapy include headache, dyspepsia, and nausea. More serious side effects such as lethal seizures or cardiac arrythmias can occur if blood levels are too high. Many derivatives of theophylline have been prepared in an effort to discover an analogue without these limitations (60,61). However, the most universal solution has resulted from the development of reHable sustained release formulations. This technology limits the peaks and valleys in semm blood levels that occur with frequent dosing of immediate release formulations. ControUed release addresses the problems inherent in a dmg which is rapidly metabolized but which is toxic at levels ( >20 7g/mL) that are only slightly higher than the therapeutically efficacious ones (10—20 p.g/mL). Furthermore, such once-a-day formulations taken just before bedtime have proven especially beneficial in the control of nocturnal asthma (27,50,62). 

In Vivo Properties. The efficacy of dalbaheptides has been assessed ia various models of experimental septicemia ia mice. In general there was good correlation between the ED qS (effective doses which prevent death ia 50% of test animals) and the MICs on test strains. Teicoplanin was very effective, ED q values ranged from 0.11 to 0.72 mg/kg sc administration for septicemias caused by S. pyogenes S. pneumoniae and S. aureu whereas for vancomycin ED qS were from 0.58 to 7.2 mg/kg (33). Eremomycin (52) had therapeutic activity 2—3 times greater than vancomycin. Therapeutic indices... 

The second-generation antidepressants, particularly RIMAs and SSRJs, are much less toxic ia overdose than the older TCAs and irreversible MAO inhibitors. However, similar to first-generation antidepressants, the therapeutic effect only becomes manifest after several weeks. Up to one-third of depressed patients are nonresponders. Ideally, an antidepressant would combine a more rapid onset of action with greater clinical efficacy and a higher responder rate, as well as even better tolerability. 

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

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