Biomedical subjects

Patricia A Fischer

Publications and source records attributed to Patricia A Fischer.

3 recordsLinked to original sources

PubMed2004

Mild hyperhomocysteinemia promotes renal hemodynamic dysfunction without histopathologic changes in adult rats.

BACKGROUND: Hyperhomocysteinemia is able to promote glomerular damage and generate tubulointerstitial lesions. These findings were reported in rats with unilateral nephrectomy or in weanling rats with normal function, two experimental models that are exposed to other concomitant vascular risk factors. The aim of this work is to study whether mild hyperhomocisteinemia per se can induce renal histopathologic changes in adults rats with normal renal function at either 10 or 44 weeks of hyperhomocysteinemia. METHODS: Two months old male Wistar rats (N= 52) were randomly allocated to either a normal control (N= 26) or hyperhomocysteinemic (N= 26) group. Control and hyperhomocysteinemic groups had free access to either tap water or homocysteine thiolactone 50 mg/kg/day, during 10 or 44 weeks. Plasma homocysteine levels were determined by a high-performance liquid chromatography (HPLC) method. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were calculated from inulin and sodium para-aminohippurate (PAH) clearance determinations. Structural renal changes were investigated in kidneys fixed by perfusion. Histopathologic and morphometric analysis were carried out by standard methods. RESULTS: Plasma total homocysteine levels were 53% (10 weeks) and 56% (44 weeks) higher in hyperhomocysteinemic group compared to the control group. GFR and RPF were significantly lower in hyperhomocysteinemic than in control group. The histopathologic and morphometric studies did not show any differences between the control and hyperhomocysteinemic rats at 10 or 44 weeks. CONCLUSION: The present results show that mild hyperhomocysteinemia is able to induce renal functional and biochemical alterations in male adult rats that are not associated with renal histopathologic changes.

Animals↗

PubMed2003

Hyperhomocysteinemia induces renal hemodynamic dysfunction: is nitric oxide involved?

Hyperhomocysteinemia is associated with endothelial dysfunction, although the underlying mechanism is unknown. Previous studies have shown that nitric oxide (NO) plays an important role in the regulation of systemic and renal hemodynamics. This study investigated whether hyperhomocysteinemia induces renal oxidative stress and promotes renal dysfunction involving disturbances of the NO-pathway in Wistar rats. During 8 wk, control (C) and hyperhomocysteinemic (HYC) groups had free access to tap water and homocysteine-thiolactone (HTL, 50 mg/kg per d), respectively. At 8 wk, plasma homocysteine concentration, renal superoxide anion (O(2)), nitrotyrosine, and nitrite+nitrate levels, and renal function were measured. To assess NO involvement, the responses to L-Arginine (L-Arg, 300 mg/kg) and N(G)-nitro-L-arginine-methyl-ester (L-NAME, 20 microg/kg per min for 60 min) were analyzed. The HYC group showed higher homocysteine concentration (7.6 +/- 1.7 versus 4.9 +/- 1.0 micromol/L; P < 0.001), (O(2) production (157.92 +/- 74.46 versus 91.17 +/- 29.03 cpm. 10(3)/mg protein), and nitrite+nitrate levels (33.4 +/- 5.1 versus 11.7 +/- 4.3 micro mol/mg protein; P < 0.001) than the control group. Western blot analyses showed a nitrotyrosine mass 46% higher in the HYC group than in the controls. Furthermore, the HYC group showed lower GFR, renal plasma flow (RPF), and higher renal vascular resistance (RVR) than the controls. After L-Arg administration, the responses of GFR, RPF, and RVR were attenuated by 36%, 40%, and 50%, respectively; after L-NAME, the responses of RPF and RVR were exaggerated by 79% and 112%, respectively. This suggests a reduced NO bioavailability to produce vasodilation and an enhanced sensitivity to NO inhibition. In conclusion, hyperhomocysteinemia induces oxidative stress, NO inactivation, and renal dysfunction involving disturbances on the NO-pathway.

Animals↗

PubMed2003

Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures.

Fosphenytoin is a phosphate ester prodrug developed as an alternative to intravenous phenytoin for acute treatment of seizures. Advantages include more convenient and rapid intravenous administration, availability for intramuscular injection, and low potential for adverse local reactions at injection sites. Drawbacks include the occurrence of transient paraesthesias and pruritus at rapid infusion rates, and cost. Fosphenytoin is highly bound (93-98%) to plasma proteins. Saturable binding at higher plasma concentrations accounts for an increase in its distribution volume and clearance with increasing dose and infusion rate. Fosphenytoin is entirely eliminated through metabolism to phenytoin by blood and tissue phosphatases. The bioavailability of the derived phenytoin relative to intravenous phenytoin is approximately 100% following intravenous or intramuscular administration. The half-life for conversion of fosphenytoin to phenytoin ranges from 7-15 minutes. Faster intravenous infusion rates and competitive displacement of derived phenytoin from plasma protein binding sites by fosphenytoin compensate for the expected conversion-related delay in appearance of phenytoin in the plasma. Unbound phenytoin plasma concentrations achieved with intravenous fosphenytoin loading doses of 100-150 or 50-100mg phenytoin sodium equivalents/min are comparable, and achieved at similar times, to those with equimolar doses of intravenous phenytoin at 50 (maximum recommended rate) or 20-40 mg/min, respectively. The rapid achievement of effective concentrations permits the use of fosphenytoin in emergency situations, such as status epilepticus. Following intramuscular administration, therapeutic phenytoin plasma concentrations are observed within 30 minutes and maximum plasma concentrations occur at approximately 30 minutes for fosphenytoin and at 2-4 hours for derived phenytoin. Plasma concentration profiles for fosphenytoin and total and unbound phenytoin in infants and children closely approximate those in adults following intravenous or intramuscular fosphenytoin at comparable doses and infusion rates. Earlier and higher unbound phenytoin plasma concentrations, and thus an increase in systemic adverse effects, may occur following intravenous fosphenytoin loading doses in patients with a decreased ability to bind fosphenytoin and phenytoin (renal or hepatic disease, hypoalbuminaemia, the elderly). Close monitoring and reduction in the infusion rate by 25-50% are recommended when intravenous loading doses of fosphenytoin are administered in these patients. The potential exists for clinically significant interactions when fosphenytoin is coadministered with other highly protein bound drugs. The pharmacokinetic properties of fosphenytoin permit the drug to serve as a well tolerated and effective alternative to parenteral phenytoin in the emergency and non-emergency management of acute seizures in children and adults.

Animals↗