Efficacy limited

The locoregional delivery and efficacy limit the potential therapeutic benefit of Ad-p53 in metastatic Stage IV NSCLC patients except perhaps in a palliative role with low-dose radiation therapy. Currently, ECOG is evaluating the feasibility of Ad-p53 (INGN 201) in combination with 30 Gy of radiation therapy for recurrent or previously radiated NSCLC. This trial initiated by Choy is the first Ad-p53 study to be performed in a cooperative group setting. 

As mentioned before, LNIT requires a particular administration technique after premedication, the allergenic extract (aqueous or powdered) has to be sprayed into a nostril while vocalizing. This fact, in addition to the efficacy limited to the nose, reduced the clinical use of LNIT therefore, no postmarketing surveillance studies are available. In conclusion, based on the clinical trials, LNIT appears safe and well tolerated. The EAACI/ESPACI position paper states that side effects do not represent a problem [12],... 

Treatment Pharmacology and positive attributes Expected efficacy Limitations... 

Much of the effort on viral insecticide research has been aimed at the development of adjuvants to improve efficacy. Although some effort has been directed at incorporation of adjuvants into the basic formulation, a majority of effort has been with spray tank adjuvants. Materials to overcome the potential efficacy limiting characteristics of the virus (e.g. stability and coverage) have been targets of research. 

Serious hepatotoxicity of tacrine has been documented. More recent data suggest, however, that this toxicity can be reduced by carehiUy monitoring semm alanine aminotransferase levels (125). The side effects of tacrine also include gastrointestinal disturbances and emesis, and alternative AChE therapies are being advanced. Velnacrine (20), a metaboUte of tacrine, was expected to have reduced hepatotoxicity. However, its limited efficacy and side-effect profile, which includes dmg-related hematological changes, caused it to be dropped from further development. 

Initial attempts to treat AD using direct cholinergic agonists were limited by low efficacy and side-effect issues (140—142). Thus trials using RS-86 (25), oxotremorine [70-22-4] (26), arecoline [63-75-2] (27), and pilocarpine [92-32-7] (28) to treat AD were equivocal (Eig. 5). However, the identification of multiple subtypes of muscarinic receptors has stimulated a search for subtype specific muscarinic agonists which may limit side effects while increasing efficacy. 

BK actions are mediated through at least two types of GPCR B and B2. At the B receptor, des-Arg BK is more potent than BK. The converse is tme at the B2 receptor. The effects of BK are primarily mediated by activation of the B2 receptor because the B receptor has limited tissue distribution and is iaduced by noxious stimuli such as apamin or an inflammatory mediator-type response. The existence of a B receptor was suggested on the basis of limited efficacy of known antagonists ia some systems. A B receptor may also exist. The human B2 receptor has been cloned. 

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). 

Just-in-Time. Just-in-time closely followed the reintroduction of SPG into the American workplace. The efficacy of JIT was limited in the United States to an emphasis on keeping component inventories low to reduce the cost of inventory (16). More importantiy, however, JIT should be used to focus management attention on quahty problems. 

Cooling water pH affects oxidizing antimicrobial efficacy. The pH determines the relative proportions of hypochlorous acid and hypochlorite ion or, in systems treated with bromine donors, hypobromous acid and hypobromite ion. The acid forms of the halogens are usually more effective antimicrobials than the dissociated forms. Under some conditions, hypochlorous acid is 80 times more effective in controlling bacteria than the hypochlorite ion. Hypochlorous acid predominates below a pH of 7.6. Hypobromous acid predominates below pH 8.7, making bromine donors more effective than chlorine donors in alkaline cooling waters, especially where contact time is limited. 

There are no hiUy effective therapeutic agents for the treatment of thederiasis. Chlorotetracycline (20) and oxytetracycline (3) have therapeutic activity duting the iacubation period. Pamaquiae (68) was reported to have a specific effect on the erythrocyctic forms. Other dmgs with limited efficacy are imidocarb (19) on T annulata halofugiaone (45) on both T annulata and T parva and the naphthoquiaones menoctone (76), parvaquone (88), and buparvaquone (89) on T parva. Methotrexate (90) has been found to be active in vitro (Table 9). 

Methybcanthine Diuretics. The mild diuretic effect of drinking coffee, from caffeine, and tea, mainly from theophylline, has been recogni2ed for along time. But the methylxanthines (Table 5) are of very limited efficacy when used as diuretics. The excretion of sodium and chloride ions are increased, but the potassium excretion is normal. Methylxanthines do not alter the urinary pH. Even though the methylxanthines have been demonstrated to have minor direct effects in the renal tubules, it is beUeved that they exert their diuretic effects through increased renal blood flow and GER (71). 

Some limitations are associated with UV radiation for disinfection. These include (1) The process performance is highly dependent on the efficacy of upstream devices that remove suspended solids (2) Another key factor is that the UV lamps must be kept clean in order to maintain their peak radiation output (3) A further drawback is associated with the fact that a thin layer of water (< 0.5 cm) must pass within 5 cm of the lamps. 

For the past few years, however, there has been a hiatus in the pace of discovery of novel medicinal agents. It has been postulated by some that the field has now slowed down due to the limitations of the almost strictly empirical approach that has been applied to date to drug development. It is possible, too, that the higher standards of efficacy and safety that a new drug must meet today, combined with the enormously increased costs of clinical trials, have acted to keep all but the most promising new drugs off the market. 

Since the corrosion resistance of anodic films on aluminium is markedly dependent on the efficacy of sealing (provided the film thickness is adequate for the service conditions), tests for sealing quality are frequently employed as an index of potential resistance to corrosion. While it is admitted that an unequivocal evaluation of corrosion behaviour can only be obtained by protracted field tests in service, accelerated corrosion tests under closely controlled conditions can also provide useful information in a shorter time within the limitations of the particular test environment employed. 

Equation 6.19 predicts an increasing IC50 with either increases in L or 1. In systems with low-efficacy inverse agonists or in systems with low levels of constitutive activity, the observed location parameter is still a close estimate of the KB (equilibrium dissociation constant of the ligand-receptor complex, a molecular quantity that transcends test system type). In general, the observed potency of inverse agonists only defines the lower limit of affinity. 

Polmar, S., Diaz-Gonzalez, F., Dougados, M., Ortiz, P., and del-Miguel, G. (2004). Limited clinical efficacy of a leukotriene B4 receptor (LTBQ antagonist in patients with active rheumatoid arthritis (RA). Arthritis Rheum. 50 S239. 

The limited efficacy of classical anticancer diugs can be explained in part by the compartment model of dividing (growth fraction, compartment A) and nondividing (compartment B) cells. The majority of antineoplastic diugs acts upon cycling cells and will hit, therefore, compartment A only. 

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

Another important issue is the size-limitation of AAV vectors the maximum size of rAAV genomes is 4.7 kb. To overcome this size constraint, dual vector systems with split-genomes have been developed [1] dual vectors are based on episomal circular multimers formed by the AAV vector genomes. However, the efficacy of the dual vector system has been questioned. 

---