Marijke Haas jimoh Akanbi

This study was designed at evaluating the acrylamide (ACR) exposure in pregnant Wistar rats as a risk of developing renal disease in their litters. Four groups of pregnant female rats were used. Group 1 control animals were given 2 ml/kg/day of distilled water. Groups 2, 3, and 4 animals were given oral gavage doses of 2, 5, and 10 mg/kg/day of ACR respectively immediately pregnancy was confirmed. Mother rats were sacrificed 10 weeks after delivery and litters were sacrificed at 13 weeks. Proteinuria was observed in ACR-treated mother rats and their litters. Serum electrolytes, urea, and creatinine values observed in the treated group were deranged for both the mothers and litters respectively. Disruption of nephrogenesis was observed in the litters of ACR-treated mother compared to the control. The results of the effect of ACR on lipid profile indicated a significant elevation in the LDL, cholesterol, and triglyceride compared to the control. There was significant reduction in the ...

Retrogradely perfused, isovolumically beating, paced rat hearts were subjected to 30 min of global ischemia in the absence and presence of nifedipine, verapamil, bepridil and quaternary bepridil at a concentration ranging from 3 to 10,000 nmol/l. Under constant pressure conditions, the arrest of coronary flow and the reduction of ventricular contraction during global ischemia were readily reversible and quickly returned at reperfusion. During ischemia, however, a diastolic contracture developed, which was slowly reversible upon reperfusion. The calcium antagonists studied appeared to delay and diminish in a concentration-dependent way the diastolic contracture during ischemia. Furthermore, they accelerated the reduction of this contracture at reperfusion. Nifedipine, bepridil and quaternary bepridil showed a 100 to 1000 times higher potency in accelerating the recovery of the diastolic contracture during the reperfusion phase than in reducing the development of diastolic tension dur...

Concentration-dependent effects of the enantiomers of the calcium antagonists, gallopamil, diltiazem, and bepridil have been studied in the Langendorff-perfused rat heart, subjected to 30 min of global ischemia. It is shown that the time course, as well as the height of the energy deprivation-induced left ventricular diastolic contracture that develops during ischemia, can be selectively inhibited by negative inotropic concentrations of the calcium antagonist enantiomers. The time needed for recovery from the diastolic contracture during the reperfusion phase can be shortened significantly by lower, vasodilating concentrations of the drugs. In normoxically perfused hearts, stereoselectivity factors (sf) of the enantiomers of the compounds amounted to 63, 10, and 2 for the negative inotropic and 12.6, 79, and 4 for the vasodilating activities of gallopamil, cis-diltiazem, and bepridil, respectively. The sf values of negative inotropism proved to be remarkably similar to sf values of 50 and 7.9 for gallopamil and cis-diltiazem in the protection of the ischemic contracture during ischemia, whereas the sf values of coronary flow increase closely paralleled the values of 7.9, 63, and 2.5 for gallopamil, cis-diltiazem, and bepridil, respectively, in protection during the reperfusion phase. The results strongly suggest that at reperfusion the vasoselective enantiomers of calcium antagonists provide protection related to improved tissue perfusion, and thereby possibly restoring the distorted ionic and energetic homeostasis, whereas the other enantiomers are more involved in a direct energy-saving activity, resulting in protection during the ischemic period.

One possibility to optimize the therapeutic application of dopaminergic compounds with a catechol function is the reversible protection of this moiety using a prodrug approach. Important features in this respect are a proper chemical stability in the gastrointestinal tract, an adequate release rate after arrival in the blood stream or the possibility to cross the blood–brain barrier. A HPLC method

Calixspherands, like 1, form kinetically stable complexes with alkali metal cations. For practical in uiuo applications coupling of these complexes with carrier molecules is mandatory. Therefore, a general method for the synthesis of functionalized calixspherand ...

... Oligonucleotides to the Proximal Tubular Cell of the Kidney Using Macromolecular and Pro-drug Approaches Marijke Haas, Yukio Kato, R. Folgert G. Haverdings, Frits Moolenaar, Kokichi Suzuki, Dick de Zeeuw, Yuichi Sugiyama, Dirk KF Meijer 5.1 Introduction ...

The mesangial cells of the glomerulus, the proximal tubular cells and the interstitial fibroblasts are the first choice targets for renal drug delivery since they play a pivotal role in many disease processes in the kidney. In the present review, only targeting to the proximal tubular cell is addressed because only this has been studied extensively. Two approaches of drug delivery to the proximal tubular cell have been studied up to now, the prodrug/softdrug and low-molecular-weight protein (LMPWP) approach. Most research on tubular specific drug delivery has focused on the development of amino-acid prodrugs that, after delivery, require activation by more or less kidney-selective enzymes. Large differences in renal selectivity are found. For some prodrugs, a rapid removal of the released drug from the kidney explained the low renal selectivity whereas for others, cleavage in non-target tissue and insufficient transport across the cell to the enzyme site seemed mainly responsible. The LMWP approach is based on drug attachment to a protein (<30 kD) that is freely filtered through the glomerulus and after accumulation is selectively catabolized in the lysosomes of the proximal tubular cell. Using LMWPs as drug carriers, a higher renal selectivity can be attained and a broader range of drugs can be attached while the rate of drug release can also be manipulated. The studies with captopril-lysozyme and naproxen-lysozyme clearly showed that targeting resulted in a higher renal selectivity and that drugs delivered into and regenerated in the proximal tubular cell exert renal selective pharmacological activity. Further testing will provide more definite data on the added value of this delivery technology.

Chapter 5 Drug-targeting to the kidney: renal delivery and degradation of a naproxen-lysozyme conjugate in-vivo Marijke Haas, Alex CA Kluppel, Ellen S. Wartna, Frits Moolenaar, Dirk KF Meijer, Paul £ de Jong and Dick de ... I I. Haas M, de Zeeuw D, van Zanten A, Meijer DKF. ...

Studies on short-term renal responses to (pharmacological) intervention require accurate and multiple collection of urine samples. Several invasive techniques have been described for frequent urine collection of the conscious rat, each having their own limitations. No data are available about the feasibility of the spontaneously voiding, freely moving rat for this purpose. In the present study, bladder voidings of six

Selective targeting of drugs to the kidney may enable an increased renal effectiveness combined with a reduction of extrarenal toxicity. Intrarenal delivery to the proximal tubular cell can be achieved using low-molecular-weight proteins, such as lysozyme. Administration of high dosages of lysozyme, required to study the effects of such conjugates in vivo, however, is restricted since a partial escape of the renal reabsorption and the occurrence of unwanted effects on systemic blood pressure and renal function may occur. The purpose of this study was to investigate the optimal parenteral administration schedule and the maximum dose of lysozyme, providing the most optimal tubular reabsorption and at the same time a minimal effect on blood pressure and renal hemodynamics, comparing continuous infusion of lysozyme with single dose injections. Urinary lysozyme excretion increased dose-dependently, both during continuous infusion and intravenous bolus injections. However, this loss of intact lysozyme into the urine was much higher after 3 injections of in total 250 mg x kg(-1) x 6 h(-1) (51.8+/-3.7% of the dose) compared to the same dose administered by continuous infusion (11.7+/-2.4%, P < 0.001). Continuous infusion of lysozyme up to 1000 mg x kg(-1) in 6 hours had no effect on systemic blood pressure, whereas a bolus injection of lysozyme (167 mg x kg(-1)) resulted in reversible blood pressure lowering of 52.2+/-2.2% (P<0.001). A dose-dependent decline of the glomerular filtration rate was observed at dosages of lysozyme higher than 100 mg x kg(-1) x 6 h(-1), with a maximal reduction of 53.0+/-3.7% after infusion of 1000 mg x kg(-1) x 6 h(-1). Effective renal plasma flow was less affected and only lowered statistically significant at dosages of 500 (-12.6+/-3.3%, P<0.05) to 1000 mg x kg(-1) x 6 h(-1) (-17.2+/-3.9%, P<0.01). We conclude that bolus injections of lysozyme should not be used for renal targeting purposes since it results in considerable tubular loss of lysozyme in the urine as well as cardiovascular side effects. In contrast, continuous infusion of lysozyme using dosages sufficient for renal drug targeting (maximally 15 mg x kg(-1) x h(-1)) only has minimal effects on blood pressure and renal hemodynamics, with a minimal urinary lysozyme loss as well.