Inactivation of creatine kinase during the interaction of mefenamic acid with horseradish peroxidase and hydrogen peroxide: participation by the mefenamic acid radical

Creatine kinase (CK) was used as a marker molecule to examine the side effects of damage to tissues by mefenamic acid, an effective drug to treat rheumatic and arthritic diseases, with horseradish peroxidase and hydrogen peroxide (HRP-H(2)O(2)). Mefenamic acid inactivated CK during its interaction with HRP-H(2)O(2). Also, diphenylamine and flufenamic acid caused a loss of CK activity, indicating the imino group, not substituent groups, in the phenyl rings have a crucial role in CK inactivation. Rapid change in mefenamic acid spectra was detected, suggesting that mefenamic acid is efficiently oxidized by HRP-H(2)O(2). Peroxidases oxidize xenobiotics to free radicals by a one-electron transfer. However, direct detection of mefenamic acid radicals by electron spin resonance (ESR) was unsuccessful. Reduced glutathione and 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) in the reaction mixture containing mefenamic acid with HRP-H(2)O(2) produced ESR signals consistent with a DMPO-glutathionyl radical adduct. These results suggest that inactivation of CK is probably caused through formation of mefenamic acid radicals. Sulfhydryl groups and tryptophan residues of CK were diminished by mefenamic acid with HRP-H(2)O(2). Other SH enzymes, including alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, were very sensitive to mefenamic acid with HRP-H(2)O(2). Inactivation of SH enzymes may explain some deleterious actions of mefenamic acid.     

Bone and joint tuberculosis: a continuing problem.

Although tuberculous disease of bones and joints is becoming uncommon, it still occurs and may cause devastating sequelae. It is frequently not diagnosed prior to the onset of permanent damage to the joints or spine; the most important reason for this delay may be the fact that it is not considered in the differential diagnosis of monoarthritis or back pain. Most persons with the disease have other evidence of tuberculosis. Not infrequently an aggressive approach (including synovial biopsy or surgical exploration of the back) is needed to confirm the diagnosis when there are no other clues.     

Intracellular magnesium in elderly patients with heart failure: Effects of diabetes and renal dysfunction

Hypomagnesemia is frequent in diabetes mellitus (DM), while renal dysfunction (RD) may be associated with hypermagnesemia. Severe cardiac arrhythmias and other adverse clinical manifestations are frequent in heart failure (HF), in DM and in RD. Depletion of intracellular magnesium (icMg), which may coexist with normal serum Mg, might contribute to these deleterious effects. However, icMg content in normomagnesemic HF patients with RD or DM has not been studied. We assessed total icMg in peripheral blood mononuclear cells (PBMC) from 80 normomagnesemic furosemide-treated HF patients who were divided as follows: subgroups A (DM), B (RD), C (DM and RD), and D (free of DM or RD). PBMC from 18 healthy volunteers served as controls. IcMg content (μg/mg cell protein) in HF was lower compared to controls (1.68±0.2 vs. 2.4±0.39, p<0.001). In the entire HF group, a significant inverse correlation was evident between icMg and serum creatinine (r=−0.37) and daily furosemide dosages (r=−0.121). IcMg in the HF subgroups A, B, C, and D was 1.79±0.23, 1.57±0.23, 1.61±0.25, and 1.79±0.39, respectively (p=0.04 between A and B, p=0.08 between B and D, and non-significant in the remaining comparisons). Serum Mg, potassium, calcium, furosemide dosages and left ventricular ejection fraction were comparable in all subgroups. In conclusion, icMg depletion was demonstrable in PBMC, which may be responsible for some of the adverse clinical manifestations in HF patients. In particular, icMg depletion in RD might contribute to cardiac arrhythmias in this patient group. Mg supplementation to normomagnesemic HF patients might therefore prove beneficial.     

Drug dosing guidelines in patients with renal failure.

The metabolism and excretion of many drugs and their pharmacologically active metabolites depend on normal renal function. Accumulation and toxicity can develop rapidly if dosages are not adjusted in patients with impaired renal function. In addition, many drugs that are not dependent on the kidneys for elimination may exert untoward effects in the uremic milieu of advanced renal disease. A familiarity with basic pharmacologic principles and a systematic approach are necessary when adjusting drug dosages in patients with abnormal kidney function. The distinct steps involve calculating the patient''s glomerular filtration rate, choosing and administering a loading dose, determining a maintenance dose, and a decision regarding monitoring of drug concentrations. If done properly, therapy in renal patients should achieve the desired pharmacologic effects while avoiding drug toxicity. Physicians must not oversimplify the pharmacologic complexities presented by patients with renal failure by relying excessively on nomograms and "cookbook" equations. In addition to a reduced glomerular filtration rate, patients with renal disease often have alterations in pharmacokinetics such as bioavailability, protein binding, hepatic biotransformation, and volume of distribution. An awareness of biologically active or toxic metabolites of parent compounds that accumulate when the glomerular filtration rate is reduced is also necessary to avoid toxicity. The effects of dialysis on drug elimination and the need for supplemental dosing are additional considerations in patients undergoing renal replacement therapy.     

Erythropoietin therapy in patients with chronic renal failure.

Symptomatic anemia is a common complication of chronic renal failure. Treatment is now possible with the availability of recombinant human erythropoietin (epoetin alfa). Previous experimental studies have suggested that correcting the anemia of chronic renal failure may be harmful in that renal failure may be accelerated. Although experience with this drug has been primarily restricted to its use in patients with end-stage renal disease, several recent trials have been reported in patients with varying degrees of chronic renal failure. We review these studies with particular reference to the progression of renal failure and the drug''s reported side effects. We conclude that the use of epoetin is beneficial and well tolerated and that there is no compelling evidence for the acceleration of renal failure associated with its use in patients.