Development anti-infective drugs

The study by Prentis et al. [4] included an analysis of 198 NCEs, developed between 1964 and 1985 by British pharmaceutical companies but had not been marketed for reasons presented in Figure 1.1. Kennedy [5] further analyzed these data and noticed that a high number of anti-infective drug development projects were all terminated... 

FDA (1992) Points to Consider on Clinical Development and Labeling of Anti-Infective Drug Products ... 

Clearly, identification of resistance mechanisms and of potential intracellular targets all lead to information which would be very useful for the development of novel anti-infective drugs by peptide-based design, once the structure of these targets is known. In addition, identification of transport proteins that may... 

Bacterial membranes have a much more complex construction than mammalian membranes. This enables bacteria to survive in the various environments of host organisms. Knowledge of the composition and functioning of bacterial membranes is therefore essential to the development of anti-infective drugs. In order to be effective, antibacterial agents not only have to have optimal pharmacokinetic properties such as uptake and distribution in the patient, but they must also be able to cross an additional barrier, the cell wall of the bacteria, so that they can reach the target site. This additional barrier is remarkable on account of its rigidity and permeability. The construction and structural uniqueness of this barrier is briefly described below. 

In Section 2.19.2 we demonstrated the invaluable role that natural products have played in the discovery and development of a wide range of anti-infective drugs, which are essential components of the physicians armamentarium. In this section we wish to highlight how nature, once more, has provided indispensable... 

As of 1995, there were 79 new, non-AIDS-related anti-infective drugs and vaccines. 28 of which were antibiotics, in development by 49 different U.S. companies (4). Additionally, 103 medicines and vaccines are currently in development for AIDS arnJ AIDS-related opportunistic infections (4). Table 3 lists a few promising anti-jnfective agents that are currently in clinical testing or that have recently entered the commercial market. A few of these are discussed in more detail in this section. 

The sulfonamides (sulfa) drug s were the first antibiotic dragp developed that effectively treated infections. Although the use of sulfonamides began to decline after the introduction of more effective anti-infectives, such as the penicillins and other antibiotics, these drug s still remain important for the treatment of certain types of infections. 

It may be possible to increase the utility of our resources to treat influenza virus infection through combinations of antiviral agents with different modes of action (discussed in Cinatl et al. 2007a De Clercq and Neyts 2007). The sialidase inhibitors, for example, may be able to be used in conjunction with the adamantane-based M2 ion channel inhibitors (Govorkova et al. 2004 Ilyushina et al. 2006), with Ribavirin (Smee et al. 2002) or with non-influenza virus specific therapeutics such as anti-inflammatory drugs (Carter 2007). Combination therapy may also reduce the potential of resistance development (Ilyushina et al. 2006). 

Aging is one of the major risk factors for developing gastric ulcers because of an increased incidence of Helicobacter pylori infections and a widely spread use of non-steroidal anti-inflammatory drugs (NSAID). Co-morbidity, with the need for prophylactic medication with antiplatelet therapy, warfarin and other anticoagulants, also increases the risk of gastrointestinal bleeding and ulcerations (Murakami et al. 1968). 

Figure 1.2 Reasons for drug development termination, excluding anti-infectives (n= 121).

Proton pump inhibitors (PPIs), such as omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole, are commonly prescribed to treat symptoms of heartburn, acid reflux, chest pain, dyspepsia, and chronic cough. PPIs inhibit the transfer of protons into the stomach lumen. Pharmacological acid suppression is thus used to treat gastroesophageal reflux disease (GERD) and esophagitis, peptic ulcers, and Helicobacter pylori infection as well as to prevent ulcer development with concurrent nonsteroidal anti-inflammatory drug use. 

Clinical success rates and attrition rates by phase of clinical trial for new drugs are important indicators of how effectively companies are utilising drug development resources. The proficiency with which this is done reflects a complex set of regulatory, economic and company-specific factors. Success rates differ by therapeutic class, and t)q)ically vary from about 28% success rate for an anti-infective compound to 12% for respiratory drugs. Table 9.3 shows the details. 

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