In vivo toleration study

Fig. 6.4 In vivo tolerance study of CAS 1609 and IS-5-MN (H. Bohn, personal communication).

Recently, chondroitin sulfate-cationized gelatin hybrid nanoparticles have been proposed for ocular gene therapy intended for topical administration. A plasmid codifying the mucin MUC5AC—essential for tear homeostasis but found at a decreased level in dry eye—was successfully transfected in vitro into cornea and conjunctiva cells [113,114]. Furthermore, these chondroitin sulfate-based nanoparticles were able to specifically transfect conjunctiva of rabbits and mice, as shown in Figure 8.6. In vitro cytoxidty and in vivo tolerance studies also showed that the system was innocuous under the conditions tested. 

After in silico and in vitro screening, short-term in vivo toleration (IVT) studies [7] are conducted to identify unexpected target organ toxicities, such as myelotoxicity and hepatotoxicity. The IVT is essentially an abbreviated version of regulatory, preclinical. 

Maisonneuve, Isabelle M., and Mary J. Krcek. 1994. "Acute Tolerance to the Dopamine Response Induced by a Binge Pattern of Cocaine Administration in Male Rats An In Vivo Microdialysis Study." Journal cf Pharmacology and Experimental Therapeutics 268 916-21. 

PYA copolymer Bioavailability enhancer Single-dose toxicity (in rat and dog) and maximum tolerated dose/short-term (2wks—oral) (in rat and dog) toxicity as well as 2 in vitro and 1 in vivo genotoxicity studies. ADME studies with 14C-labelled material are underway and a 3-6 mo toxicity study in the rat is planned No adverse effects seen to date 41... 

Nectrisine also has anti-viral activity and inhibits the retrovirus Friend leukaemia virus in vivo in mice and can potentiate the activity of AZT (zidovudine) [103]. Synergistic activity has also been shown when castanospermine and AZT are used in combination therapy in vitro [104], In vivo combination studies with V-butyl-deoxynojirimycin and AZT in human patients mdicated anti-viral activity but caused diarrhoea, abdominal pain and weight loss [103], Chemical modification of V-butyl-deoxynojirimycin to make it better tolerated was suggested. 

A review is given of classic foreign body responses to polymeric drug delivery devices with emphasis on the central nervous system response. In vivo biocompatibility studies of implanted drug carriers are summarised to illustrate the behaviour of different classes of polymers and the methodologies used to evaluate their tolerance. 150 refs. 

In vivo pharmacological studies have indicated that resveratrol has a neuroprotective effect, including reduced lipid, peroxidation and neurological cell destruction, attenuation of induced lesion areas, induced tolerance to brain injury, reduced frequency of seizures, impaimient of motor coordination, and enhancement of learning [111]. 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Several aspects of the problem of herbicides being contaminated with nitrosamines, and the resulting inadvertent introduction of nitrosamines into the environment, will be discussed in other papers in this symposium. Unrecognized until less than five years ago, the situation has inspired intense debate and prompted several of the environmental chemistry studies mentioned in this paper. Like the presumed threat from the in vivo nitros-ation of pesticide residues, discussions sometimes lack the type of anticipated dose and effect calculations just mentioned. Unlike the active ingredients, whose benefits can justify residue tolerances and acceptable daily intakes, nitrosamine contaminents afford no known benefits, and the desirability of minimizing their levels is undisputed. 

Anandamide, in vivo, was shown to produce the four characteristic effects of cannabimimetics, namely, analgesia, hypothermia, hypoactiv-ity, and catalepsy (Smith, 1994 Fride, 1993 Crawley, 1993). These four effects are not unique to cannabimimetics when they are produced together, however, they are highly predictive of cannabimimetic activity (Martin, 1991). Anandamide was found to be less potent than delta-9-THC in producing these behavioral effects in mice (Fride, 1993). It has quicker onset and shorter duration of action, the latter because of rapid catabolism. Cross-tolerance studies, in which pretreatment of mice with delta-9-THC produced tolerance to most of the pharmacological effects of anandamide and vice versa, indicate that both drugs act on the same receptor (Jarbe, 1998). 

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