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The high dose in this study, 40 mg/kg/week (administered on days 1, 3, 5, 7, 14, 21, and 28), produced a typical pattern of vacuoles and minimal proximal tubular degeneration after a month of treatment [62]. There was mild vacuolation and tubular epithelial cell degeneration at the 40 mg/kg/week dose level with no evidence of other tubular or glomerular changes. In this study, there was a thorough evaluation of the standard markers of renal function as well as detailed assessment of tubular epithelial cell function.
The only change associated with these histologic changes at the higher doses is a low incidence of mild increase in urine protein. The proteinuria was measured as an increase in the protein/creatinine ratio from approximately 0.2 at baseline to 1.2. Electrophoretic characterization of protein excreted in monkeys treated with oligonucleotides has been shown to be composed of low-molecular-weight proteins, and are best correlated with the degree of tubular degeneration [61, unpublished Isis Pharmaceuticals, Inc.].
With the exception of these changes in protein excretion, there were no other functional changes observed. There were no changes in mean serum creatinine or blood urea nitrogen (BUN) and no changes in electrolytes.
Effective renal plasma flow rate and glomerular filtration rate were unchanged in treated monkeys and there were no changes in the excretion of substrates for tubular reabsorption, including glucose, amino acids, or 2-microglobulin [62]. Nor were there treatmentrelated changes in typical markers of tubular damage such as N-acetyl glucosaminidase (NAG). Stresses such as water deprivation and glucose challenge were also assessed and there were no changes in concentrating ability and threshold for glucose spillage in the kidneys of treated monkeys even at the highest dose of 40 mg/kg/week.
These data represent the best assessment possible of renal and tubular epithelial cell function and clearly demonstrate that there are no functional changes associated with the high concentration of generic cialis in tubular epithelium or cytoplasmic vacuolation. The slight increase in low-molecular-weight protein was correlated with minimal degenerative changes in epithelial cells.
Table 12.7 Reversibility of Histologic Changes in Monkeys Treated with 10 mg/kg/week ISIS 113715 for Importantly, there has been no suggestion of altered glomerular morphology or function in the studies performed in monkeys with ISIS 113715.
The supporting data includes routine histologic, ultrastructural, clinical pathology, and urinalysis evaluation at doses up to 20 mg/kg/week administered for 13 weeks or 40 mg/kg/week administered for 4 weeks. Additionally, the glomerular filtration rate was assessed as part of the renal physiology study at 40 mg/kg/week. The absence of apparent changes in glomerular morphology or function is consistent with the relative concentration of generic cialis in the cortex, which is much higher in tubular epithelium than glomerulus [57,59]. Reversibility of Renal Effects in the Monkey The morphologic changes in tubular epithelium observed in monkeys are reversible.
In monkeys treated with ISIS 113715, the basophilic granules, cytoplasmic vacuolation, and tubular epithelial cell degenerative changes reverse with the cessation of treatment and the clearance of drug from the kidney (Table 12.7). The clearance rate is closely correlated with the rate of generic cialis clearance from kidney. Proximal tubular epithelium normally undergoes a normal turnover process, and so is easily capable of recovering once drug is cleared.
