**13. Conclusions**

Acute poisoning with metal phosphides, particularly aluminium phosphide, is a worldwide problem most commonly encountered in the Indian Sub-Continent. The clinical features have been well described though it is only recently that the mechanisms of toxicity have been more clearly understood. Poisoning from phosphides is mediated by phosphine which has been shown to rapidly perturb mitochondrial morphology, inhibit oxidative respiration, and cause a severe drop in mitochondrial membrane potential. This failure of cellular

Aluminium Phosphide Poisoning 355

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respiration is likely to be due to a mechanism other than inhibition of cytochrome C oxidase as phosphine inhibits cytochrome C oxidase activity less dramatically *in vivo* than *in vitro*  and only partially inhibits cytochrome C oxidase activity in humans. Phosphine can also form the highly reactive hydroxyl radical and inhibit both catalase and peroxidase leading to lipid peroxidation. The gas or gases given of in addition to phosphine when phosphide formulations come into contact with water or acid need to be identified and their toxicity determined. The observation that both aluminium and phosphine may inhibit acetylcholinesterase activity needs to be investigated further as does the report that the administration of atropine and pralidoxime reduces morbidity and mortality in aluminium phosphide poisoning. There is conflicting evidence also on the occurrence and clinical importance of magnesium disturbances which some have described. The benefit of magnesium supplementation has still to be determined.

## **14. References**


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**16** 

*Japan* 

*1Nagoya University,* 

**Application of a New Genotoxicity Test System** 

**with Human Hepatocyte Cell Lines to Improve** 

**the Risk Assessment in the Drug Development** 

A typical testing scheme for a small-molecule therapeutics (outlined in Fig. 1) begins with a large number of compounds and high-throughput assays (Kramer et al., 2007). As the number of viable lead molecules is reduced, incrementally more predictive but lower throughput assays identify those leads with the most drug-like properties and optimal in vitro and in vivo efficacy. Confirmed hit compounds identified in high-throughput screens are evaluated for potency, selectivity, ADME (absorption, distribution, metabolism and excretion), physical and chemical properties, and activity in relevant animal models (Fig. 1). This testing paradigm typically delivers drug-like compounds that have promising pharmacokinetic parameters and efficacy in preclinical models within a 1–2-year cycle time. Compounds that successfully meet preclinical efficacy, ADME, pharmacokinetics and safety criteria are nominated as candidates for formal development. Historically, the move from discovery to development consisted of a discreet hand-off from the 'discovery' organization to the 'development' organization, and little preclinical safety assessment was performed on lead molecules beyond a few basic in vitro toxicity assays. As toxicity is a primary cause for compound attrition and long development (Kola & Landis, 2004), companies in the past 5– 10 years have increasingly integrated safety assessment principles into earlier phases of the

Also as shown in Fig.1, the costs of R & D for a drug in 2001 were of the order of US \$802 million (DiMasi et al., 2003); current estimates are closer to about US \$900 million; Considerably more of these costs are incurred later in the pipeline, and most of the attrition occurs during full clinical development (Phases II and III). In the other literature, it has been estimated that the average cost associated with the discovery and preclinical evaluation of a

Kola and Landis researched the reason why compounds undergo attrition and how this has changed over time (Kola. & Landis, 2004). In 1991, adverse pharmacokinetic and bioavailability results were the most significant cause of attrition and accounted for ~40% of all attrition. However, in 2000 the major causes of attrition in the clinical trials were lack of efficacy (accounting for approximately 30% of failures) and safety (toxicology in preclinical

**1.1 Current situation in the development of pharmaceuticals** 

single drug candidate were US \$620 million (Rawlins, 2004).

**1. Introduction** 

drug discovery process.

Tsuneo Hashizume1,2 and Hiroaki Oda1

*2Takeda Pharmaceutical Company Limited,* 

