Therapeutic Indications

The pain associated with diabetic peripheral neuropathy, trigeminal neuralgia, or cancer may predispose such patients to depression. Tricyclic antidepressants have been shown to be an effective adjunct in managing these and other similar conditions. 

Some episodic phobias are regarded as masked depression and thus respond to treatment with tricyclic antidepressants. 

Fluoxetine, in addition to its antidepressant property, has been used as an appetite suppressant. Imipramine and desipramine have been used as antibulimic substances. 

Desipramine has been used as part of the treatment of alcoholism. Because depression has led to relapsed drinking in people suffering from alcoholism who are striving to maintain sobriety, treatment with antidepressants may reverse or prevent these depressive symptoms. They may also correct the biochemical abnormalities hypothesized to underlie both depression and alcoholism, thus helping to ensure abstinence in recovering alcoholics. 

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The following chemical databases are available for searching in MACCS-II. ChemicalDirectoy Database contains a combined catalogue of 66 commercial suppHers of more than 77,000 organic chemicals. AL4.CCS-II Drug Data eport based on the Prous Dmg Data Report, includes 39,000 compounds with information on therapeutic indication, biological action, phase of development, related patents, and Hterature references. MUSE Database the tutorial database for MACCS-II, contains over 100 compounds. 

Morphine has certain undesirable side effects. Among these are respiratory depression, nausea, and vomiting, depression of the cough reflex, cardiovascular depression and hypotension, smooth muscle contraction (constipation), and histamine release (93). Morphine s onset of action, duration, and low therapeutic indices have prompted a search for a more effective opiate iv anesthetic. Extreme simplification of the complex morphine molecule has resulted in anilido —piperidines, the fentanyl class of extremely potent opiate iv anesthetics (118,119). 

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... 

Most peptide antibiotics have been isolated from Jictinomycetes and especially from Streptomjces. Many P-lactams, however, and a few other useful peptide antibiotics have come from fungi. These streptomycete and fungal peptide antibiotics include many stmctural types having varied therapeutic indications and/or scientific appHcations. 

Currently, baclofen is the only clinically used GAB Ab receptor agonist. It is used as a muscle relaxant for treatment of spasticity in spinal injury and multiple sclerosis. The cloning of GABAb receptors has renewed the interest in the search for more selective diugs and novel therapeutic indications. 

Clinical Particulars (therapeutic indications, administration, contraindications, special warnings and precautions, interaction with other drugs, use in pregnancy or lactation, effects on driving, undesirable effects, overdose)... 

New therapeutic indication +1 (human) to +3 (veterinary) 3 from approval of indication... 

In the US, a manufacturer may not submit an application that relies on data from an approved submission for a period of 5 years after the reference product was authorised, unless the owner of the original data has granted a right of reference. The FDA may not approve an application that relies on data submitted as a supplement (e.g. new therapeutic indication) to an authorised drug for a period of 3 years after approval ofthe supplement. These exclusivity periods will be extended by 6 months if the reference submissions contain paediatric data. The FDA will also not... 

Homeopathic registration Yes Yes (Manufacture, control and stability) No (Sufficient dilution) No (No therapeutic indications)... 

A variety of other clinically important infections, such as brucellosis, listeriosis, salmonellosis, and various Mycobacterium infections, are of interest as these are often localized in organs rich in MPS cells. Liposome encapsulation has been demonstrated to improve therapeutic indices of several drugs in a number of infectious models. The natural avidity of macrophages for liposomes can also be exploited in the application of the vesicles as carriers of immunomodulators to activate these cells to an microbicidal, antiviral, or tumoricidal state. These studies were recently reviewed by Emmen and Storm (1987), Popescu et al. (1987), and Alving (1988). In addition to the treatment of "old" infectious diseases, the concept of MPS-directed drug delivery is of considerable interest for the therapy AIDS, possibly enabling control of human immunodeficiency virus replication in human macrophages. 

The clinician should bear in mind the toxic potential for the various antidepressant medications when patients already have or develop suicidality. The TCAs and MAOIs have narrow therapeutic indices, whereas the SSRIs, SNRIs, nefa-zodone, and mirtazapine have wide therapeutic indices.22... 

Laboratory data may consist of many different collections of tests, such as ECG laboratory tests, microbiologic laboratory tests, and other therapeutic-indication-specific clinical lab tests. However, laboratory data traditionally consist of results from urinalysis, hematology, and blood chemistry tests. Traditional laboratory data can come from what are called local laboratories, which are labs at the clinical site, or from central laboratories where the clinical sites send their samples for analysis. Often when the laboratory data come from a central laboratory, there is no physical CRF page for the data and they are loaded into the clinical data management system directly from an electronic file. Local laboratory data may be represented with a CRF page such as this ... 

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

We have endeavored, too, to approach biological activity in the same fashion as we did earlier. The first time some therapeutic indication occurs will be the occasion for a concise simplified discussion... 

In another study, the carrier protein was replaced by an enzyme compatible solid-phase resin (PEGA), and enzyme-catalyzed cyclization was used to probe substrate specificity. This study demonstrated also that oxo-esters are tolerated as substrates for TE domains, and then-preparation in library format served as an excellent tool for substrate specificity studies, as well as for preparation of cyclized peptides. Figure 13.11 shows how the TycA TE showed selectivity for only residues 1 and 9 (colored in red), and changes at all other residues were tolerated [42]. Hydrogen bonding interactions are shown in green. Several compounds made from this series were shown to demonstrate improved therapeutic indices (with respect to hemolysis) while retaining antimicrobial activity. 

Genetic variants resulting in an unintended action of a drug outside of its therapeutic indication (Idiosyncratic)... 

Drug Molecular formula Molecular mass Therapeutic indication... 

Longer-term carcinogenicity tests are undertaken, particularly if (a) the product s likely therapeutic indication will necessitate its administration over prolonged periods (a few weeks or more) or (b) if there is any reason to suspect that the active ingredient or other constituents could be carcinogenic. These tests normally entail ongoing administration of the product to rodents at various dosage levels for periods of up to (or above) 2 years. 

Overall, therefore, a range of growth factors may demonstrate potential in wound manage-ment/healing, or for other therapeutic indications. A summary of these factors and their biological activities/potential, therefore, constitutes the remainder of this chapter. 

Table 13.2 Monoclonal/engineered antibodies thus far approved for medical use. The sponsoring companies and therapeutic indications are also listed...

The blood is generally warmed to 37 °C immediately prior to transfusion. Whole blood is often used to replace blood lost due to injury or surgery. The number of units (one unit equals approximately 510 ml) administered depends upon the health and age of the recipient, along with the therapeutic indication. Administration of whole blood may also be undertaken to supply a recipient with a particular blood constituent (e.g. a clotting factor, immunoglobulin, platelets or red blood cells). However, this practice is minimized, in favour of direct administration of the specific blood constituent needed. 

The desire to achieve at least such minimal therapeutic indices and to also identify levels associated with toxicity (and the associated toxic effects) form the basis of dose selection for systemic (and most other in vivo) toxicity studies. 

Initial therapeutic exploratory studies may use a variety of study designs, including concurrent controls and comparison with baseline status. Subsequent trials are usually randomized and concurrently controlled to evaluate the efficacy of the drug and its safety for a particular therapeutic indication. Studies in Phase II are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population, and are closely monitored. 

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