Chimpanzee

A large number of a-hydroxybenzylbenzimidazole [50-97-5] (HBB, 39), C24H22N2O, derivatives has been prepared and extensively studied as selective inhibitors of the RNA containing enterovimses (91). Although none of these derivatives have shown any antiviral activity in animals, l,2-bis(5-methoxy-2-benzimidazol-2-yl)-l,2-ethanediol [16656-27-2] (40), C2gH2gN404, was found to be active against an experimentally induced rhino vims infection in chimpanzees (92). However, the in vivo antiviral efficacy was accompanied by significant toxicity. 

Human Chimpanzee Sheep Rattlesnake Carp Garden snail Tobacco hornworm moth Baker s yeast (iso-1) Cauliflower... 

Furthermore, as shown in Figure 5.28, the number of amino acid differences between two cytochrome c sequences is proportional to the phylogenetic difference between the species from which they are derived. The cytochrome c in humans and in chimpanzees is identical human and another mammalian (sheep) cytochrome c differ at 10 residues. The human cytochrome c sequence has 14 variant residues from a reptile sequence (rattlesnake), 18 from a fish (carp), 29 from a mollusc (snail), 31 from an insect (moth), and more than 40 from yeast or higher plants (cauliflower). 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

The Merck compound MK-0608 is a 2 -C-Me-7-deaza-adenosine analog, which has recently been reported to show a 5.7 log drop in viral load in HCV-infected chimpanzees after dosing QD at 2mg/kg (Olsen 2006). An efQcient and practical process for preparing kilogram quantities has been described (Bio et al. 2004). The 12-step synthesis provides an impressive 35% overall yield and starts from the inexpensive diacetone-D-glucose. The synthesis features a novel acyl migration in route to prepare the key crystalline furanose diol intermediate (Fig. 5). The conditions... 

HBV-based vectors efficiently target quiescent hepatocytes and HBV-specific promoter and enhancer elements allow hepatocyte specific gene expression (Protzer et al. 1999). In addition, a very favorable ratio of infectious to defective particles renders HBV-based vectors good candidates for liver-directed gene transfer. Improved HBV vectors, in which HBV gene expression was abolished (Untergasser and Protzer 2004), were used in chimpanzees to treat chronic HCV infection and did not show any toxicity (Shin et al. 2005). 

The hepatitis B virus (HB V) does not grow in tissue culture and an acceptable animal model has been found to be the chimpanzee. This is observed for clinical infection after inoculation with treated and untreated virus, care being taken in the test series that residual disinfectant is removed by adequate means before inoculation into the animal. 

Muller WF, Coulston F, Korte F. 1982. Comparative metabolism of " C-trichloroethylene in chimpanzees, baboons, and rhesus monkeys. Chemosphere 11 215-218. 

Evidence suggests that HIV in humans is the result of cross-species transmission from primates infected with simian immunodeficiency virus (SIV). HIV-2 is closely related to the SIV found in sooty mangabeys in West Africa, and HIV-1 is similar to the SIV found in chimpanzees. The earliest known human HIV infection was in central Africa in 1959. Cultural practices such as the preparation and eating of bush-meat, or keeping primates as pets, may have allowed the virus to transmit from animal to human. The rapid spread of the virus throughout the world can be primarily attributed to high mobility due to modern transportation, sexual promiscuity, and drug abuse. 

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

P17. van der Poll, T., Levi, M Van Deventer, S. J., Ten Cate, H., Haagmans, B. L., Biemond, B. J., Buller, H. R Hack, C. E., and Ten Cate, J. W., Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. Blood 83,446-451 (1994). 

The starting material will likely be contaminated by intact, viable hepatitis B viral particles (and perhaps additional viruses, such as HIV). This necessitates introduction of stringent purification procedures to ensure complete removal of any intact viral particles from the product stream. A final product QC test to confirm this entails a 6-month safety test on chimpanzees. 

Much of the preclinical data generated with regard to these vaccines entailed the use of one of two animal model systems simian immunodeficiency virus infection of macaque monkeys and HIV infection of chimpanzees. Most of the positive results observed in such systems have been in association with the chimp-HI V model. However, no such system can replace actual testing in humans. 

Young, L.A., N.P. Lung, R. Isaza, and D. Heard. 1994. Anemia in a chimpanzee (Pan troglodytes) associated with lead toxicity and uterine leiomyoma. Proc. Amer. Assoc. Zoo Veterin. 1994 287. 

Priliximab (cM-T412) is an anti-CD4 chimeric monoclonal antibody that was evaluated in the clinic for the treatment of autoimmune diseases. Priliximab binds to CD4 on the surface of T cells and leads to a profound and sustained decrease in circulating CD4+ T cells decreased counts have been reported to be below normal levels at 18 and 30 months following single- and multiple-infusions.81 Similar findings were observed in preclinical studies in chimpanzees.82 The administration of priliximab was also associated with a cytokine-release syndrome that caused transient fever, myalgia, chills, headache, nausea, and/or hypotension that was accompanied by an increase in serum IL-6. Although evidence of efficacy was observed in clinical trials for CD, the... 

Struthers E.J. and Campbell, J. (1996) Scent specific behavioural responses to olfactory enrichment in captive chimpanzees (Pan troglodytes). XVI Congress International Primatological Society, Madison, WI. Abstracts p. 762. 

Ostrower, S. and Brent, L. (1997) Olfactory enrichment for captive chimpanzees responses to different odours. Laboratory primate newsletter 36, 8-10. 

No counterpart to the Hp polymorphism found in humans has been observed in animals. Most of the mammalian species studied-chimpanzee, baboon, monkey, horse, cow, pig, seal, rabbit, squirrel, arctic marmot rat, guinea pig, and mouse—have haptoglobins similar to human type 1-1. Sometimes double Hp bands have been found—monkey, marmot, seal, and mouse (A5, A8, B7, B9, Ml, M5). 

In paragraph 3, what conclusion can be reached about the chimpanzee s ability to use a tool ... 

Some biotechnologically derived pharmaceuticals will cross-react with species that can be evaluated toxicologically, while others cross-react only with nonhuman primates such as the chimpanzee, a protected species. In this case, a well-designed safety, or Phase 0 study at doses higher than the proposed clinical dose may provide valuable safety information. However, a lack of cross-reactivity with any nonhuman species does not necessarily make preclinical safety evaluation impossible, not does it limit toxicity testing to species in which the protein lacks relevant pharmacological activity. Some alternative possibilities are summarized in Table 12.9. 

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