Therapeutic index drug

As introduced in Chapter 1, there are many limitations associated with conventional drag therapy. An intravenously administered drag is subject to a number of pharmacokinetic processes in vivo which can decrease the drugs therapeutic index, including ... 

Shaw IC. 1987. MESNA and oxazaphosphorine chemotherapy [Abstract], In Anticancer Drugs Therapeutic Index Improvement by Toxicity Reduction, April 6-7, 1987, London, Westminster Hospital, Imperial Cancer Research Fund, and Deutsches Krebsforschungszentrum, A4.2. 

Fig. 1. Blood—drug concentration curve used to determine bioavailabiLitv and bioequivalence. C is the maximum dmg concentration in the blood and corresponds to some The AUC (shaded) represents the total amount of orally adininistered dmg the time from points A to B represents dmg onset, from points B to D, the duration MEC = minimum effective concentration MTC = minimum toxic concentration and TI = therapeutic index.

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Uracil is used more effectively, in nucleic acid synthesis within a rat hepatoma than in normal liver. This observation appears to have stimulated the synthesis of 5-fluorouracil (1027) as an antimetabolite mainly because the introduction of a fluorine atom involves a minimal increase in size. In the event, 5-fluorouracil did prove to have antineoplastic activity and it is now a valuable drug for treatment of tumors of the breast, colon or rectum, and to a lesser extent, gastric, hepatic, pancreatic, uterine, ovarian and bladder carcinomas. As with other drugs which interfere with DNA synthesis, the therapeutic index is quite low and great care is required during treatment (69MI21301). 

The single dose of a drug is mo.stly derived from experience it is only possible in a very few cases to calculate it from the activity of the constituents. However, as many herbal drugs arc only weakly active and contain non-toxic substances, i.e, the therapeutic index is large, exceeding the dose is usually only of minor significance nevertheless, the pharmacist must know what the exceptions are in this book, the sections on Side effects and Making the tea draw particular attention to such cases, c.g. arnica flowers, liquorice root, etc. 

Therapeutic index. Ratio between the median lethal dose CLDso) and the median effective dose CED30) of a drug. 

Encapsulation of cDDP in liposomes did not show such favorable effects. Liposome encapsulation of cDDP decreased the antitumor effect (Fig. 9). It was demonstrated that administration of cDDP liposomes resulted in a lower incidence as well as reduced severity of focal alterations of the epithelium of the proximal tubuli compared to administration of the free drug (Steerenberg et al., 1988). However, despite this reduction in renal toxicity the therapeutic index... 

This leads to the concept of therapeutic index. The potency of a drug is almost irrelevant. It is its specificity that matters. Thus if two drugs A and B are effective at the same dose in a patient, say 1 mg, but A produces toxic effects at 10 mg which are only seen with 500 mg of B then B is clearly a much safer drug than A, in that patient. The ratio of toxic to effective dose is the therapeutic index (TI). It is often expressed as... 

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. It is important for clinicians to understand AF, because it is associated with substantial morbidity and mortality and because many strategies for drug therapy are available. Drugs used to treat AF often have a narrow therapeutic index and a broad adverse effect profile. 

Theophylline is also considered an alternative to inhaled corticosteroids for the treatment of mild persistent asthma however, limited efficacy compared to inhaled corticosteroids, a narrow therapeutic index with life-threatening toxicity, and multiple clinically important drug interactions have severely limited its use. Theophylline causes bronchodilation through inhibition of phosphodiesterase and antagonism of adenosine and appears to have anti-inflammatory and immunomodulatory properties as well.36... 

Theophylline is a non-specific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle resulting in bronchodilation. It has a modest bronchodila-tor effect in patients with COPD, and its use is limited due to a narrow therapeutic index, multiple drug interactions, and adverse effects. Theophylline should be reserved for patients who cannot use inhaled medications or who remain symptomatic despite appropriate use of inhaled bronchodilators. 

Provide a specific interaction between the delivery and biological systems such as site-specific targeting, regional delivery, or localized delivery to improve the therapeutic index of a drug. 

In summary, there are numerous variables to be adjusted and many choices of excipients required when tailoring a formulation of a particular therapeutic agent for ophthalmic application. But ultimately the choice rests on finding an economically viable formulation that clinically enhances the therapeutic index for that drug. 

Benet and Goyan [34] have presented a clear exposition on bioequivalence and narrow therapeutic index drugs. Among other papers of relevance to this topic are those by Tsang and coworkers [35], el-Tahtawy and associates [36], and Midha and collaborators [37],... 

It is unfortunate that the debate over narrow therapeutic index (ratio) or critical care drugs has been... 

M. Burns, Management of narrow therapeutic index drugs, J. Thromb. Thrombolysis, 7, 137 (1999). 

The partitioning of the activated inhibitor between direct covalent inactivation of the enzyme and release into solution is an important issue for mechanism-based inactivators. The partition ratio is of value as a quantitative measure of inactivation efficiency, as described above. This value is also important in assessing the suitability of a compound as a drug for clinical use. If the partition ratio is high, this means that a significant proportion of the activated inhibitor molecules is not sequestered as a covalent adduct with the target enzyme but instead is released into solution. Once released, the compound can diffuse away to covalently modify other proteins within the cell, tissue, or systemic circulation. This could then lead to the same types of potential clinical liabilities that were discussed earlier in this chapter in the context of affinity labels, and would therefore erode the potential therapeutic index for such a compound. 

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