Preclinical Studies in Animals

The polymerase chain reaction (PCR) is an alternative to bacterial cloning. This is a method of gene amplification that does not require living cells it takes place in vitro and can produce (in a cost-effective way) commercial quantities of pure potential medicines. 

Synthetic oligonucleotides are being developed to target defined sites on DNA sequences or genes (double-strand DNA triplex approach) or messenger RNA (antisense approach) so that the production of disease-related proteins is blocked. These oligonucleotides offer prospects of treatment for cancers and viruses without harming healthy tissues.8,9 

Gene therapy of human genetic disorders is a strategy in which nucleic acid, usually in the form of DNA, is administered to modify the genetic repertoire for therapeutic purposes, as in cystic fibrosis.10 

Understanding the molecular basis of immune responses has allowed the definition of mechanisms by which cellular function is altered by local hormones or autacoids in infections, cancer, autoimmune diseases, and organ transplant rejection. These processes present targets for therapeutic intervention. 

A number of drugs reach a delicate state of patent by 2005. Therefore, an alternative is required for new drug development the formulation of drugs into separate delivery mechanisms, often known as drug delivery systems. Clearance for these innovative formulations as abbreviated new drug applications (ANDA) is easier, compared with a new drug entity that requires approval of the United States Food and Drug Administration (USFDA). 

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Bugelski PJ, Treacy G. Predictive power of preclinical studies in animals for the immunogenicity of recombinant therapeutic proteins in humans. Curr Opini Mol Ther 2004 6(l) 10-6. 

Preclinical Studies in Animal Models of Tumor Cure... 

The last step of the drug discovery process involves the testing of lead compounds to address issues such as efficacy, bioavailability, and safety. Testing may include in vitro assays but ultimately would require a suitable disease model and studies in animals. Many compounds may need to be designed and synthesized to identify the one compound with all the desired properties. Such a compound can be advanced to preclinical studies and eventually to the clinic. 

After one or more lead compounds have been selected for further development, more preclinical investigations are needed before it is possible to start studies in humans. The main studies during this phase are toxicity studies in animals. It is important to note that the goal of these studies is not so much to find safe compounds and rejecf unsafe ones, but rather to learn under which conditions a potentially beneficial compound can be harmful, and to find out how it can be used safely in humans, if at all. Details on the type, duration and extent of toxicity studies needed can be found in various regulatory guidelines issued by ICH, FDA and EMEA and are easily accessible via the internet sites of these bodies. Although there are still differences in the requirements... 

Oligomers of perfluorohexyl-ethene fulfilled these expectations in all preclinical studies, in vitro tests as well in animal tests. A radical polymerisation, followed by ultra-purification steps, created a crystal clear gel-like substance. The behaviours of the mixture of dimeric, trimeric and tetrameric star-shaped species with an inner core of hydrocarbon bonds and an outer layer of perfluoro-alkyl chains could be adjusted by the ratio of the dimeric, trimeric and tetrameric species, using a thin layer distillation. In dependence on this ratio, the viscosity could be adjusted in the range between 90 mPas and 1700 mPas, the specific density between 1.60 g/ml and 1.66 g/ml and the interfacial tension against water between... 

Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation of therapy. Other potential adverse effects include headache and asthenia. Tenofbvir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D, and preclinical studies in several animal species have demonstrated bone toxicity (eg, osteomalacia). Monitoring of bone mineral density should be considered with long-term use in those with risk factors for or with known osteoporosis, as well as in children. Reduction of renal function over time, as well as cases of acute renal failure and Fanconi s syndrome, have been reported in patients receiving tenofovir alone or in combination with emtricitabine. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. 

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