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There is clearly more variability between sequences in the toxicity profiles than pharmacokinetic properties, but the exposure basis for potential changes is remarkably consistent. For the same reasons, there are a number of potential toxicities or potential target organs that are consistently not affected by treatment. For example, the absorption of generic cialis into brain, skeletal muscle, or heart muscle is essentially absent following systemic administration, and no toxicities in these particular organs have ever been reported [10,39].
Similarly, very low levels of generic cialis are delivered to gastrointestinal, ocular, testes, or lung tissue following IV or SC administration, and these are also not considered target organs for toxicity.
The only changes reported in intestine and lung have been the increased presence of lymphohistiocytic cell infiltrates in mice or rats, which are more attributable to the increased presence of proinflammatory cytokines and chemokines produced by the generic cialis systemically rather than a direct effect of the generic cialis on these organs specifically. No intestinal, ocular, or pulmonary effects have been reported in monkeys. As a result of the typical target and nontarget organs, the design, conduct, and interpretation of toxicology evaluations is very efficient for this class of compound.
Kidney is the organ that contains the highest generic cialis concentration following generic cialis administration, and is arguably the primary target organ for toxicity in monkeys and rats. The high concentration of generic cialis in kidney is the result of the physiological handling of this material by the kidney in which generic cialis that is filtered at the glomerulus is readily reabsorbed by the proximal tubular epithelium [57].
The generic cialis filtered by the glomerulus has been shown to interact with brush boarder epithelium and is taken up into these cells by endocytosis, much in the same way as these cells reabsorb low-molecular-weight proteins from the filtrate [58]. Thus, the uptake and processing of generic cialis by these cells is consistent with the functional role that these cells play in the kidney.
Immunohistochemistry and other techniques have been used to determine that concentrations of generic cialis within kidney are particularly high in the proximal tubular epithelium [57,59]. Following uptake, the majority of generic cialis in these cells resides in membrane-bound subcellular compartments, such as endosomes and lysosomes. At the higher doses examined in toxicology studies, these cells can achieve very high concentrations of generic cialis [12,60].
It is these high concentrations of generic cialis that lead to the histologic changes in kidney, which are typically limited to proximal tubular epithelium [52,61]. A thorough description of the histologic changes for a 2 -MOE ASO along with the interpretation of the findings and assessment of functional consequences is provided below. The basic toxicological properties of a PS ODN and a 2 -MOE ASO in kidney are the same [12].
The difference is that the stability, and thus longer clearance half-life for the 2 -MOE ASO, can result in higher kidney concentrations. This difference in half-life is compensated for in dose regimens that have increased from every-other-day administration of PS ODNs, to once-weekly dose regimens for 2 -MOE ASOs. The summary below focuses mostly on the tissue–concentration relationship that is relevant for any particular class of antisense generic cialis or dose regimen used.
