Other Therapeutic Applications

As additional information about the physiological role of NO is accumulated, new ideas and strategies for the use of NO donors are emerging. For example, several studies have demonstrated the importance of NO in penile erection (Rajfer et al., 1992 Burnett et al., 1992), and it is possible that selective delivery of NO, through the use of NO donors, may improve erectile function in impotent men. Stief etal. (1992) have shown that intracavernosal injections of 0.1-1 mg of linsidomine in patients with erectile dysfunction produced dose-dependent erectile responses with no systemic or local side effects. Porst (1993) has also shown linsidomine injection to be useful in producing penile erection, but not as effective as injected prostaglandin Ei. Further studies to optimize NO delivery for erectile responses appear to be warranted. 

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Mitragotri, S. 2005. Healing sound The use of ultrasound in drug delivery and other therapeutic applications. Nat Rev Drug Discov 4 255. 

The antianxiety effects of chlordiazepoxide (165) were described in 1960 and this compound was followed by diazepam (135). These two drugs have captured 75% of the market for sedatives in the USA. Other benzodiazepines used as antianxiety agents include oxazepam (166 R = H), a metabolite of diazepam that is better tolerated, lorazepam (166 R = Cl) and potassium clorazepate (167). Prazepam is the iV-cyclopropylmethyl analogue of diazepam. The benzodiazepines have other therapeutic applications, many being used for inducing sleep, diazepam and nitrazepam are anticonvulsants and flurazepam (168) is both an antianxiety agent and a potent hypnotic. Thieno- and pyrazolo-1,4-diazepinones isosteric with diazepam have similar pharmacological properties (B-81 Ml 10604). 

The ability of conotoxins to selectively block ion channels and neuronal receptors has led to their development into therapeutic agents. So far, most conotoxin applications as therapeutics have been concentrated on the treatment of different forms of pain. The first drug of marine origin is based on the w-conotoxin MVIIA for the treatment of chronic pain (see helow). Other therapeutic applications of conotoxins include treatment of schizophrenia, epilepsy, neuromuscular disorders, certain types of cancer, urinary dysfunction, Parkinson s disease, Alzheimer s disease, stroke, and related hrain injuries. Other uses include muscle relaxants, anesthetics, and antiseizure compounds. As the demand for new painkillers and other neuropharmacological agents is expected to increase, the value of the discovery and testing of new conotoxins is expected to continue to expand. 

BKCa The diversity of BKCa channels can be attributed to the assembly of pore-forming a subunit together with four different auxiliary subunits ((31 -(34). BMS-204352 has been identified as a BKCa channel opener for the treatment of acute ischemic stroke although it has also been shown as an M-channel activator. Therapeutic applications for channel openers include epilepsy, bladder overactivity, asthma, hypertension, and psychosis. Other known BKCa channel openers include NS-8, NS-1619, NS-4, and certain aminoazaindole analogs. 

When the antitumor activity of cisplatin was discovered, several research groups started to investigate the possible therapeutic applications of other metal-based, often organometallic, compounds. The organotin(lV) compounds that were first tested were those that were available or easily synthesized, like tri- or diorganotin(rV) halides. 

Note The three reagents should be applied as quickly as possible after each other. In combination with the Ry value, and with UV detection before application of the reagent sequence this procedure allows the identification of therapeutic quantities of thiazide diuretics and methyldopa in urine together with a series of other therapeutic agents. Mobile phase residues e. g. acetic acid, should be completely removed from the chromatograms before application of the reagent sequence. 

FAAH was originally purified and cloned from rat liver microsomes and is able to catalyse the hydrolysis of anandamide and 2-AG, in addition to other long-chain fatty acid amides [25]. Studies into the structure and role of this enzyme have generated interest in the potential therapeutic applications of FAAH inhibitors [26-28]. FAAH knock-out mouse brains contained 15-fold higher levels of anandamide than their wild-type counterparts and these animals have also been shown to be more responsive to exogenously administered anandamide [29]. These animals also showed a reduced response to painful stimuli, supporting the hypothesis that FAAH inhibition may provide novel analgesics. Levels of 2-AG were not elevated in the FAAH knock-out animals, apparently due to the existence of alternative metabolic fates for this compound [30]. 

When realistic quantities of the natural prostaglandins became available, their extreme potency and wide-ranging biological activities were discovered and visions of therapeutic application in the regulation of fertility, control of ulcers, blood pressure, bronchial asthma, and many other conditions led to a torrent of chemical and biological studies which currently measures about four papers daily, and at least one a week dealing with synthesis alone. 

In other cases, the widespread application of a biopharmaceutical may be hindered by the occurrence of relatively toxic side effects (as is the case with tumour necrosis factor a (TNF-a, Chapter 9). Finally, some biomolecules have been discovered and purified because of a characteristic biological activity that, subsequently, was found not to be the molecule s primary biological activity. TNF-a again serves as an example. It was first noted because of its cytotoxic effects on some cancer cell types in vitro. Subsequently, trials assessing its therapeutic application in cancer proved disappointing due not only to its toxic side effects, but also to its moderate, at best, cytotoxic effect on many cancer cell types in vivo. TNF s major biological activity in vivo is now known to be as a regulator of the inflammatory response. 

IGF I has recently been the focus of considerable interest due to its actions on motor neurons. It can prevent normal motor neuron cell death during development, reduce the loss of these cells following nerve injury and enhance axonal regeneration. In the adult, injection of IGF I results in sprouting of motor neuron terminals and increases the size of the neuromuscular junction. These and other studies suggest potential therapeutic applications of IGF I in several neurological diseases including amyotrophic lateral sclerosis and peripheral neuropathies. 

This study also provides evidence of the applicability of DFT to other therapeutic fields involving enzymes and prodrugs, e.g. 

O. Lopez and M. Bols, Isofagomine, neouromycin and other 1-azasugars, imino sugars-related glycosidase inhibitors, in Imino sugars, from synthesis to therapeutic applications, ed. P. Compain and O. Martin, Wiley, 2007, pp. 131-151. 

Interest in dendritic polymers (dendrimers) has grown steadily over the past decade due to use of these molecules in numerous industrial and biomedical applications. One particular class of dendrimers, Starburst polyamidoamine (PAMAM) polymers, a new class of nanoscopic, spherical polymers that appears safe and nonimmunogenic for potential use in a variety of therapeutic applications for human diseases. This chapter will focus on investigations into PAMAM dendrimers for in vitro and in vivo nonviral gene delivery as these studies have progressed from initial discoveries to recent animal trials. In addition, we will review other applications of dendrimers where the polymers are surface modified. This allows the opportunity to target-deliver therapeutics or act as competitive inhibitors of viral or toxin attachment to cells. 

These four studies on functionalized CNTs may differ from each other because their functionalized groups may have a strong influence on the behavior of CNTs in mice. Despite these differences, the pharmacokinetic profiles provided are valuable in the development of diagnostic and therapeutic applications for CNTs (Deng et al., 2007 Helland et al., 2007). 

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