NO clinical applications

I.6.I. Radioactive Isotopes. The administration of isotopically labeled drugs is now commonplace in the experimental pharmacology of every new therapeutic agent (K18, M4) but has little or no clinical application. It often provides much of the initial information about the pharmacokinetics upon which subsequent clinical practice depends, but... 

The current ARBs are selective for the ATi receptor. Since prolonged treatment with the drugs disinhibits renin secretion and increases circulating Ang II levels, there may be increased stimulation of AT2 receptors. This may be significant in view of the evidence that activation of the AT2 receptor causes vasodilation and other beneficial effects. AT2 receptor antagonists such as PD 123177 are available for research but have no clinical applications at this time. 

Natural product with antibiotic 1976 activity, but no clinical application... 

Histamine is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and possibly neurotransmission in parts of the brain. Histamine has no clinical applications, but agents that interfere with the action of histamine (antihistamines) have important therapeutic applications. 

The bulk of repetitive analyses can now be made by machines, and the clinical chemist is free to explore new areas using techniques and instruments not previously applied to clinical chemistry. This exploration starts in the laboratory by investigating the feasibility of a new analysis. In many cases this is determined by the availability of suitable instrumentation. If the test is feasible, and trials show that it provides clinically useful information, it will be applied routinely, and the instrumentation may then require modification or mechanization to deal with larger numbers of specimens. Relatively few analyses, once they have become feasible, have been rejected as having no clinical application the enthusiast will always hope that an application will be found or that refinements in the method will reveal one. There is thus a danger that the mere availability of a test, particularly if performed by an instrument, will create its own demand. 

P2-selective antagonists, if specific enough, would be useful as research tools to delineate the role p2-adrenoceptors play in greater detail even though presently no clinical applications for such compounds are apparent. The first compound to have this property was oc-methyl DCI. 

Vasoactive intestinal peptide (VIP) is an extremely potent vasodilator but is probably more important as a neurotransmitter. It is found in the central and peripheral nervous systems and in the gastrointestinal tract. No clinical application has been found for this peptide. 

Substance P is another neurotransmitter peptide with potent vasodilator action on arterioles. However, substance P is a potent stimulant of veins and of intestinal and airway smooth muscle. The peptide may also function as a local hormone in the gastrointestinal tract. Highest concentrations of substance P are found in those parts of the nervous system that contain neurons subserving pain. At the present time, there are no clinical applications for substance P or its antagonists. However, capsaicin, the hot component of chili peppers, releases substance P from its stores in nerve endings and depletes the peptide. Capsaicin has been approved for topical use on arthritic joints and for postherpetic neuralgia. 

Other tissues The effects of these drugs on the heart are discussed in Chapter 14 (see class I antianhythmic agents). Most local anesthetics also have weak blocking effects on skeletal muscle neuromuscular transmission, but these actions have no clinical application. The mood elevation induced by cocaine probably reflects actions on dopamine or other amine-mediated synaptic transmission in the CNS rather than a local anesthetic action on membranes. 

In vivo bioassays Although this method is close to reality, it has many disadvantages, including that it is not applicable for all vitamins, is time consuming, is an indirect method, is expensive, and has no clinical application [21]. 

A potential area of interest which has as yet had no clinical application is the approach of rendering a thrombus fibrin more susceptible to fibrinolysis, and is treated in a comprehensive review on factor XIII inhibition.95... 

Rifampin (4,2ob)y discussed in Section 4.0, inhibits replication of vaccinia virus in mouse cells (Heller et a/., 1969). Also rifamycin SV (4.20a) inhibits reverse transcriptase, the RNA-dependent synthesizer of DNA in viruses. Unfortunately, no clinical applications of these discoveries have been made. Apart from these and the phleomycins (Section 4.0, p. 115), antiviral action has rarely been found among antibiotics. 

No ligands of IP3R have yet found clinical application. Most agonists of IP3R are either modifications of DP3 or derived from adenophostin A. The only known antagonists of IP3R (e.g., heparin, 2-AJPB) are vety poorly selective. 

IMS is a new, developing technique to visualize biomolecule maps in tissue. IMS has opened a new frontier in medicine as well as in clinical applications. Lipids and low-molecular-weight compounds in tissue sections cannot be observed with conventional microscopic or electron microscopic techniques therefore, no distribution map of these molecules in a tissue structure has been described in the scientific literature or in medical textbooks. However, IMS is bringing to light the characteristic distribution map of lipids (Fig. 21.11) this map made a major impact to lipid research. 

The application for a clinical trial authorisation (CTA) for the first administration of a NME to man comprises the same elements as all other CTAs but, of course, there will be no clinical data. The regulatory authority known as the competent authority (CA) of the EU member state requires receipt of confirmation of the EU clinical trials database (EUDRACT) number, a covering letter, a completed application form, the protocol with all current amendments, the IB and a full Investigational Medicinal Product Dossier (IMPD) (see below). If the study is to be conducted in more than one member state, a list of CAs should be included. If the opinion of the lEC is available, it should be provided. 

The functional effects of glycosylation take on added significance in the context of producing gonadotrophins by recombinant means. As subsequently discussed, several are now produced for clinical application in recombinant (animal cell line) systems. While the glycosylation patterns observed on the recombinant molecules can vary somewhat in composition from those associated with the native hormone, these slight differences bear no negative influence upon their clinical applicability. 

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