Current Drug Discovery Technologies - Volume 1, Issue 4, 2004

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs / biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) 1,000,000. MCASE / MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by ≥4 ADR reports and ≥20,000 shipping units during five years of marketing, and an RI ≥4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Mycobacterium avium-intracellulare complex (MAC) infections are frequently encountered in immunocompromised hosts, especially AIDS patients, although nodular-bronchiectasis type MAC infections without predisposing conditions are steadily increasing, particularly in Japan. Clinical control of MAC infection is difficult, since it responds poorly to available antimycobacterial regimens because of the intrinsic resistance of MAC organisms to common antituberculosis drugs, although some antimycobacterial drugs, such as macrolides (clarithromycin, azithromycin), ethambutol, clofazimine and rifamycins (especially rifabutin), are fairly or modestly effective in controlling AIDS-associated MAC bacteremia. In addition, treatment of pulmonary MAC infections is also difficult, even with available antimycobacterial multi-drug therapies. The insufficient efficacy of the majority of ordinary antimycobacterial drugs in treating MAC diseases is principally due to the low susceptibility of MAC to the majority of ordinary antimycobacterial drugs, the extremely wide range of susceptibilities of MAC isolates to most antimicrobial drugs, and the fact that polyclonal MAC infections are occasionally seen in AIDS patients. Therefore, the development of new antimicrobials and administration protocols that are safe and potently effective against MAC infections is urgently needed. However, despite the gradual but steady increase in the incidence of MAC infections, and thereby the urgent call for new drug development, new drugs that are truly useful for the treatment of refractory MAC diseases continue to elude us. In this review article, the following topics will be described: (1) the present status of the existing anti-MAC drugs, with special reference to the recent findings of the in vitro and in vivo anti-MAC activities of macrolides and other moderately useful drugs, such as new rifamycins, clofazimine and some fluoroquinolones, and (2) the present status and future prospects of the development of new promising antimicrobials with anti-MAC activity.

Microdialysis has been developed during the last 25 years by several authors primarily to study brain function and changes in levels of endogenous compounds such as neurotransmitters or metabolites. The development of microdialysis for the purpose of measuring drugs was initiated during the late eighties. This technique provides a means of continuous plasma sampling without repeated blood sampling and the applicability to the study of drug metabolism and pharmacokinetics in experimental animals and human. Also, the microdialysis technique allows the study of plasma protein binding and the saturation of protein binding. The implantation of the microdialysis probe in other tissues and organs, like central nervous system, adipose tissue and heart, allows the study of drug distribution. On the other hand, the measurement of endogenous substances using the microdialysis technique permits the study of the effect of drugs on neurotransmission and metabolism. Moreover, as this technique allows the simultaneous determination of different physiological parameters such as blood pressure, locomotor and convulsive activity, it is a suitable tool for pharmacokinetic-pharmacodynamic studies of drugs and pharmacokinetic-pharmacodynamic (PK-PD) modeling. Lastly, the reverse microdialysis is a powerful technique for the study of local actions of drugs in different tissues such as specific brain nuclei, myocardium, liver or skeletal muscle. So, this article reviewed the vast applications of the microdialysis technique for the study of pharmacokinetic and pharmacodynamic properties of drugs.

The human genome project has been completed, but the function of many genes is unknown. It is, therefore, necessary to elucidate the function of a large number of genes within a short time. To achieve this goal, materials are needed that condense or package DNA into nano-particles that can easily be taken up by cells and would allow DNA to be retained without degradation. Atelocollagen is a reliable carrier for gene delivery because it is considered safe and appropriate for practical use [1-5]. We developed a basic technique for high-throughput gene transfer and expression screening by pre-coating a multi-well plate with an Atelocollagen/DNA complex in which cells are then seeded [6]. Complexes with a nano-particle form were efficiently transduced into cells without the use of additional transfection reagents, and they allowed for long-term gene expression. The complex spotted onto the well of a plate was stable for a long period and allowed the cells to transduce and express reporter genes. We also showed that the present method with Atelocollagen-based gene transfer is applicable to gene medicines, such as antisense ODNs, siRNA, and adenovirus vectors. These results suggest that an Atelocollagen-based cell transfection array may be appropriate for general use in the high-throughput screening of large sets of gene medicines with functions in mammalian cells.

Drug discovery in the pharmaceutical industry has shown great demands for screening absorption, distribution, metabolism, excretion (ADME) and pharmacokinetics (PK) in guiding the selection of lead candidate compounds. Determination of ADME/PK properties of new chemical entities (NCE) in early drug discovery should allow defects to be corrected prior to time-consuming and expensive preclinical and clinical development stages. Mass spectrometry has evolved to become an irreplaceable technology in all types of drug discovery applications because of its high sensitivity, speed, selectivity, versatility, and ease of automation. This review will include current mass spectrometric techniques and applications in drug discovery, as well as future prospects.