Human beings, testing

The chloride and chromate are also important compounds. Zinc is an essential element in the growth of human beings and animals. Tests show that zinc-deficient animals require 50 percent more food to gain the same weight as an animal supplied with sufficient zinc. 

Platinum—polyethyleneimine complexes prevent the division of bacteria, and are being tested as carriers in the treatment of cancer and vimses (445—447). Encapsulated PEIs containing nucleic acid bases activate the neutrophils in human blood (448). 

Health and Safety Factors. Sodium metabisulfite is nonflammable, but when strongly heated it releases sulfur dioxide. The oral acute toxicity is slight and the LD q (rat, oral) is 2 g/kg. Sodium bisulfite appears to be weakly mutagenic to some bacteria, ia rodent embryos, and ia a human lymphocyte test. There is iaadequate evidence for carciaogenicity (183,343). 

Relatively Httie is known about the bioavailabiUty of pantothenic acid in human beings, and only approximately 50% of pantothenic acid present in the diet is actually absorbed (10). Liver, adrenal glands, kidneys, brain, and testes contain high concentrations of pantothenic acid. In healthy adults, the total amount of pantothenic acid present in whole blood is estimated to be 1 mg/L. A significant (2—7 mg/d) difference is observed among different age-group individuals with respect to pantothenic acid intake and urinary excretion, indicating differences in the rate of metaboHsm of pantothenic acid. 

Anesthetics. Ethyl amiaobenzoate [94-09-7] (benzocaiae), C2H22NO2, is the only anesthetic candidate that might allow spawned-out broodstock carcasses to be used for pet or human food. Studies are still required to determine which residues remain ia the carcasses (9). Electronarcosis is an alternative to chemical anesthesia that uses varying electrical frequencies to rapidly anesthetize fishes and allow gentie recovery. Electronarcosis has been used effectively on tilapia (Oreochromis sp.) and the common carp Cyprinus carpid) and the technique is being tested with other fishes (23,24). 

Neoprene Type TW was shown to have low oral toxicity in rats. The LD q was found to be in excess of 20,000 mg/kg. Human patch tests with Types GN, W, WRT, and WHV showed no skin reactions (169). The FDA status of Du Pont Neoprene polymers is described (172). Although polychloroprene itself has not been shown to have potential health problems, it should be understood that many mbber chemicals that may be used with CR can be dangerous if not handled properly. This is particularly tme of ethylenethiourea curatives and, perhaps, secondary amine precursors often contained in sulfur modified polychloroprene types. Material safety data sheets should be consulted for specific information on products to be handled. 

Kulstad and Malmsten tested a number of derivatives of l,10-diaza-18-crown-6 (9) for toxicity in mice (intravenous). Compound 9 and the bis-N-2-hydroxyethyl,bis-N-2-carboxamidomethyl, and bis-N-2-carboxymethyl derivatives of 9 were tested and all were found to be toxic in the range of 5—50 mg/kg. At a dose level of 5 mg/kg of 9, the two mice tested were still alive after a week, but at a dose level of 25 mg/kg, the mice died in less than 24 h If these data could be translated directly to human beings, a 100 kg human would require something between 0.5—2.5 g of compound (i.v.) to produce a lethal effect. 

The radiation hazard associated with fallout from nuclear weapons testing arises from radioactive isotopes such as these. One of the most dangerous is strontium-90. In the form of strontium carbonate, SrC03, it is incorporated into the bones of animals and human beings, where it remains far a lifetime. 

The cl mg discovery process can be envisioned as four interconnected phases (see Figure 8.1). Generally, these are the acquisition of chemicals to be tested for biological activity, the determination of the activity of those chemicals on biological systems (pharmacodynamics), the formulation of the most active of these for therapeutic testing in humans (pharmaceutics), and the determination of adequate delivery of the active drug to diseased tissues (pharmacokinetics). Each of these collections of processes is interconnected with the others and failure in any one of them can halt the development process. It is worth considering each process separately, as well as the relationships between them. 

A related strategy would be to inactivate the 5-HTib/id autoreceptors which are found on serotonergic nerve terminals and so prevent feedback inhibition of 5-HT release in the terminal field. These drugs would not prevent the impact of indirect activation of 5-HTia receptors, and the reduced neuronal firing, by SSRIs (described above), but they would augment 5-HT release in the terminal field once the presynaptic 5-HTia receptors have desensitised. Selective 5-HTib/id antagonists have been developed only recently but will doubtless soon be tested in humans. 

Experimental evidence in humans is based upon intervention studies with diets enriched in carotenoids or carotenoid-contaiifing foods. Oxidative stress biomarkers are measured in plasma or urine. The inhibition of low density lipoprotein (LDL) oxidation has been posmlated as one mechanism by which antioxidants may prevent the development of atherosclerosis. Since carotenoids are transported mainly via LDL in blood, testing the susceptibility of carotenoid-loaded LDL to oxidation is a common method of evaluating the antioxidant activities of carotenoids in vivo. This type of smdy is more precisely of the ex vivo type because LDLs are extracted from plasma in order to be tested in vitro for oxidative sensitivity after the subjects are given a special diet. 

Extraction procedures must be adjusted when separated anthocyanins will be tested in biological studies. We have found that the types of acids used for anthocyanin extraction as well as their residual concentrations in the final extract may affect the results obtained from biological tests. The growth inhibitory effect of anthocyanins on HT29 (human colonic cancer) cells may be overestimated if the residual acid in the extract exerts a toxic effect on the cells. Acetic acid residues in anthocyanin extracts showed less toxicity to HT29 cells than hydrochloric acid when samples were prepared under the same extraction procedure and subjected to the same tests on HT29 cells. In addition, the procedure to remove acids affected the acid residual concentration as well in final anthocyanin extracts, with lyophilization being more successful than rotary evaporation. 

If the product is to be used for pharmaceuticals the GMP rules must be obeyed during plant operation. All chemicals to be tested in clinical studies with humans must be prepared according to GMP. This leads to very detailed documentation since if you haven t documented it, you haven t done it . All procedures for manufacturing and changes in procedures are subject to approval by quality control departments. This decreases the flexibility in process development. Products that are contaminated too much must be reprocessed according to the GMP guidelines. All equipment to be used in the pilot plant must be validated before use. 

Of ultimate importance are the full reports of the clinical studies in humans and their results. These data will be treated statistically for their validity. The number of studies for a specific compound or combination of compounds will vary with the type of drug being tested, as will the number of tests needed to appraise relative or absolute safety and to clearly demonstrate efficacy. The basic requirement is the proof of safety and efficacy of the product being submitted under the NDA system. A drug that does not contribute to therapy, such as a new antihistamine that does not demonstrate greater safety or efficacy, or both, compared with drugs already on the market, will have a difficult or impossible time achieving approval. 

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