Defining hypercalciuria in nephrolithiasis.

The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid.

Drug dosing in patients with impaired renal function.

Renal function can affect disposition and response to drugs in a variety of ways. This review discusses the principles underlying such responses, with particular emphasis on how changes in disposition parameters affect dosing decisions.

Factors associated with exacerbation of heart failure include treatment adherence and health literacy skills.

We determined the factors associated with exacerbation of heart failure, using a cohort (n = 192) nested within a randomized trial at a university-affiliated ambulatory practice. Factors associated with emergency or hospital care included left ventricular ejection fraction, hematocrit and serum sodium levels, refill adherence, and the ability to read a prescription label. Refill adherence of <40% was associated with a threefold higher incidence of hospitalization for heart failure than a refill adherence of >or=80% (P = 0.002). In multivariable analysis, prescription label reading skills were associated with a lower incidence of heart failure-specific emergency care (incidence rate ratio, 0.76; 95% confidence interval (CI), 0.19-0.69), and participants with adequate health literacy had a lower risk of hospitalization for heart failure (incidence rate ratio, 0.34; 95% CI, 0.15-0.76). We conclude that inadequate treatment adherence and health literacy skills are key factors in the exacerbation of heart failure. These findings emphasize the need for careful instruction of patients about their medications.

Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure.

PURPOSE: Because the bioavailability of oral furosemide is erratic and often incomplete, we tested the hypothesis that patients with heart failure who were treated with torsemide, a predictably absorbed diuretic, would have more favorable clinical outcomes than would those treated with furosemide. PATIENTS AND METHODS: We conducted an open-label trial of 234 patients with chronic heart failure (mean [+/- SD] age, 64 +/- 11 years) from an urban public health care system. Patients received oral torsemide (n = 113) or furosemide (n = 121) for 1 year. The primary endpoint was readmission to the hospital for heart failure. Secondary endpoints included readmission for all cardiovascular causes and for all causes, numbers of hospital days, and health-related quality of life. RESULTS: Compared with furosemide-treated patients, torsemide-treated patients were less likely to need readmission for heart failure (39 [32%] vs. 19 [17%], P <0.01) or for all cardiovascular causes (71 [59%] vs. 50 [44%], P = 0.03). There was no difference in the rate of admissions for all causes (92 [76%] vs. 80 [71%], P = 0.36). Patients treated with torsemide had significantly fewer hospital days for heart failure (106 vs. 296 days, P = 0.02). Improvements in dyspnea and fatigue scores from baseline were greater among patients treated with torsemide, but the differences were statistically significant only for fatigue scores at months 2, 8, and 12. CONCLUSIONS: Compared with furosemide-treated patients, torsemide-treated patients were less likely to be readmitted for heart failure and for all cardiovascular causes, and were less fatigued. If our results are confirmed by blinded trials, torsemide may be the preferred loop diuretic for patients with chronic heart failure.

Renal effects of cyclooxygenase-2 selective inhibitors.

Recent in-vitro and animal data show that cyclooxygenase-2 has an integral role in the physiology and pathophysiology of the kidney. Cyclooxygenase-2 regulates renin-angiotensin secretion, and thereby glomerular filtration rate and sodium homeostasis. It is also important for protecting against hypertonic stress. As a consequence, it is not surprising that clinical data verify that selective inhibitors of cyclooxygenase-2 affect renal function to a degree similar to that which has previously been documented with nonselective nonsteroidal anti-inflammatory drugs.

Reliability and validity of the compliance belief scales among patients with heart failure.

BACKGROUND: Lack of medication and dietary compliance leads to troublesome symptoms and hospitalization in patients with heart failure. Compliance behaviors are influenced by beliefs about the behavior. OBJECTIVE: The purpose of this study was to evaluate the reliability and validity of the Beliefs about Medication Compliance Scale (BMCS) and the Beliefs about Dietary Compliance Scale (BDCS) among patients with heart failure. THEORETICAL FRAMEWORK: This study's theoretical framework is the Health Belief Model. METHODS: A convenience sample of 234 patients with heart failure completed the BMCS and the BDCS. Patients completed the scales at baseline by face-to-face interviews and at 8 and 52 weeks after baseline by telephone interview. RESULTS: Construct validity of the scales was supported by confirmatory factor analysis. Both the BMCS and the BDCS had benefits and barriers scales with clear factor loadings. The internal consistency reliability estimates of the scales ranged from.63 to.88, with the BMCS having some estimates lower than.70. The test-retest reliability estimates ranged from.07 to.57. The intraclass correlation coefficient estimates were higher between the 8-week and 52-week scores for all scales. Possible reasons for the varying estimates are discussed. CONCLUSIONS: The BMCS and the BDCS have documented reliability and validity. Future work should be directed at evaluating the responsiveness of the scales to changing patient conditions and testing interventions to improve medication and dietary compliance through changing beliefs.

Renal effects of COX-2-selective inhibitors.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) effectively treat a variety of inflammatory diseases, these agents may cause deleterious effects on kidney function, especially with respect to solute homeostasis and maintenance of renal perfusion and glomerular filtration. NSAIDs act by reducing prostaglandin biosynthesis through inhibition of cyclooxygenase (COX) which exists as two isoforms (COX-1 and COX-2). NSAID-induced gastrointestinal toxicity is generally believed to occur through blockade of COX-1 activity, whereas the anti-inflammatory effects of NSAIDs are thought to occur primarily through inhibition of the inducible isoform, COX-2. However, the situation in the kidney may be somewhat different. Recent studies have demonstrated that COX-2 is constitutively expressed in renal tissues of all species; this isoform may, therefore, be intimately involved in prostaglandin-dependent renal homeostatic processes. Drugs that selectively inhibit COX-2 might, therefore, be expected to produce effects on renal function similar to nonselective NSAIDs which inhibit both COX-1 and COX-2. This assertion is borne out by recent clinical studies showing that the COX-2 inhibitors rofecoxib and celecoxib procedure qualitative changes in urinary prostaglandin excretion, glomerular filtration rate, sodium retention, and their consequences similar to nonselective NSAIDs. It, therefore, seems unlikely that these COX-2 inhibitors (and perhaps their successors) will offer renal safety benefits over nonselective NSAID therapies, and, at this juncture, it is reasonable to assume that all NSAIDs, including COX-2-selective inhibitors, share a similar risk for adverse renal effects.

Social support and health-related quality of life in chronic heart failure patients.

OBJECTIVES: Objectives of this study were to: (1) describe perceived social support during a baseline hospitalization and 12 months later among heart failure patients; (2) examine differences in social support as a function of gender and age (less than 65 and 65 years or older); and (3) examine social support as a predictor of health-related quality of life. BACKGROUND: Social support is a predictor of well-being and mortality, but little is known about support patterns among heart failure patients and how they influence quality of life. METHODS: The sample included 227 hospitalized patients with heart failure who completed the Social Support Survey and the Chronic Heart Failure Questionnaire at baseline; 147 patients completed these questionnaires again 12 months after baseline. RESULTS: Mean baseline and 12-month total support scores were 56 and 53, respectively, with a score of 76 indicating the most positive perceptions of support. The ANOVA indicated significant interactions of gender by age for total (F = 5.04; p = 0.03) and emotional/informational support (F = 4.87; p = 0.03) and for positive social interactions (F = 4.43; p = 0.04), with men under age 65 perceiving less support than men aged 65 and older and women in either age group. Baseline support did not predict 12-month health-related quality of life, but changes in social support significantly predicted changes in health-related quality of life (R2 = 0.14). CONCLUSIONS: Overall, perceptions of support were moderate to high, but there was wide variation in perceptions over time. Men under age 65 reported less support than other groups of patients. Importantly, changes in social support were significant predictors of changes in health-related quality of life.

Intravenous diltiazem and CYP3A-mediated metabolism.

AIMS: To study whether intravenous diltiazem, a calcium channel blocker commonly prescribed for hypertension and stable angina, is an inhibitor of the CYP3A enzymes by using oral lovastatin, an HMG Co-A reductase inhibitor, as a substrate. METHODS: Ten healthy volunteers were studied in a randomized two-way crossover design. The two arms were 1) administration of a 20 mg dosage of lovastatin orally and 2) administration of a 20 mg dosage of lovastatin orally 1 h after an intravenous loading dosage and constant infusion of diltiazem. Blood samples were collected up to 25 h in order to quantify lovastatin and diltiazem concentrations in the separated serum. Lovastatin and diltiazem concentrations were quantified by GC-MS and h.p.l.c., respectively. RESULTS: Intravenous diltiazem did not significantly affect the oral AUC, Cmax, t(1/2), or tmax of lovastatin. CONCLUSIONS: These data suggest that the interaction of lovastatin with diltiazem does not occur systemically and is primarily a first-pass effect. Thus, drug interactions with diltiazem may become evident when a patient is moved from intravenous to oral dosing.

Healthcare costs of patients with heart failure treated with torasemide or furosemide.

OBJECTIVE: To compare the direct healthcare costs of patients with congestive heart failure (CHF) prescribed torasemide (torsemide) or furosemide (frusemide). DESIGN AND SETTING: As part of a prospective, randomised, nonblind study, we assessed the effects of torasemide and furosemide on readmission to hospital in 193 patients treated for CHF at a US urban public healthcare system. We also calculated total direct healthcare costs for the 2 drugs. The perspective of the analysis was that of the healthcare system. Healthcare charge and utilisation data, demographic information, and health status data were obtained from an electronic database containing data for all patients treated within the healthcare system. PATIENTS AND PARTICIPANTS: Upon admission to the hospital, patients were eligible if they had evidence of left ventricular systolic dysfunction, were at least 18 years old, and were receiving furosemide. INTERVENTION: Inpatients were randomised to either torasemide or furosemide treatment for 1 year. MAIN OUTCOME MEASURES AND RESULTS: Patients treated with torasemide had fewer hospital admissions than those treated with furosemide [18 vs 34% for CHF (p = 0.013) and 38 vs 58% for any cardiovascular cause (p = 0.005)]. In the torasemide group, expected annual hospital costs per patient were lower for CHF admissions (by $US1054; 1998 values) and for all cardiovascular admissions (by $US1545) than in the furosemide group. Because the annual acquisition cost of torasemide was $US518 per patient higher than that of furosemide, the resulting net cost saving per patient was $US536 for CHF and $US1027 for all cardiovascular causes. Outpatient costs did not differ between treatment groups regardless of whether drug costs were considered. Total direct costs were $US2124 lower with torasemide than with furosemide (not statistically significant). CONCLUSIONS: Owing largely to reduced readmission to the hospital, the cost of inpatient care for patients with CHF is significantly lower with torasemide than with furosemide, despite the higher acquisition cost of torasemide. Treatment with torasemide resulted in a nonsignificant reduction in total direct costs (outpatient plus inpatient) compared with furosemide.

Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial.

BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1), whose inhibition is associated with gastrointestinal ulceration, and COX-2, whose inhibition is associated with therapeutic benefits. Although agents that do not produce COX-1 activity may have fewer adverse effects, targeted disruption of the COX-2 allele in mice has resulted in severe renal problems, suggesting that COX-2 inhibition may also produce adverse effects. OBJECTIVE: To determine the effect of rofecoxib, a member of the coxib class of drugs and a specific inhibitor of the COX-2 enzyme, on renal function in elderly patients. DESIGN: A randomized, three-period, single-dose crossover study and a randomized, parallel-group, multiple-dose study. SETTING: Clinical research units. PATIENTS: 75 patients 60 to 80 years of age. INTERVENTION: In the first study, single doses of rofecoxib, 250 mg (about 5-fold to 20-fold the recommended dose); indomethacin, 75 mg; and placebo were administered to 15 patients. In the second study, multiple doses of rofecoxib, 12.5 or 25 mg/d; indomethacin, 50 mg three times daily; or placebo were administered to 60 patients. Patients in both studies received a low-sodium diet MEASUREMENTS: Glomerular filtration rate, creatinine clearance, and urinary and serum sodium and potassium values. RESULTS: Compared with placebo, single doses of rofecoxib and indomethacin decreased the glomerular filtration rate by 0.23 m/s (P < 0.001) and 0.18 mL/s (P = 0.003), respectively. In contrast, respective decreases of 0.14, 0.13, and 0.10 mL/s were observed after multiple doses of rofecoxib, 12.5 mg/d (P = 0.019); rofecoxib, 25 mg (P = 0.029), and indomethacin (P = 0.086) were administered. Changes in creatinine clearance and serum and urinary sodium and potassium were less pronounced. CONCLUSIONS: The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.

The interaction of diltiazem with simvastatin.

BACKGROUND: Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that is used as a cholesterol-lowering agent and is metabolized by cytochrome P450 3A (CYP3A) enzymes. Diltiazem is a substrate and an inhibitor of CYP3A enzymes and is commonly coadministered with cholesterol-lowering agents such as simvastatin. The objective of this study was to quantify the effect of diltiazem on the pharmacokinetics of simvastatin. METHOD: A fixed-order study was conducted in 10 healthy volunteers with a 2-week washout period between the phases. In one arm of the study, a single 20-mg dose of simvastatin was administered orally; the second arm entailed administration of a single 20-mg dose of simvastatin orally after 2 weeks of treatment with 120 mg diltiazem twice a day. RESULTS: Diltiazem significantly increased the mean peak serum concentration of simvastatin by 3.6-fold (P < .05) and simvastatin acid by 3.7-fold (P < .05). Diltiazem also significantly increased the area under the serum concentration-time curve of simvastatin 5-fold (P < .05) and the elimination half-life 2.3-fold (P < .05). There was no change in the time to peak concentration for simvastatin and simvastatin acid. CONCLUSION: Diltiazem coadministration resulted in a significant interaction with simvastatin, probably by inhibiting CYP3A-mediated metabolism. Concomitant use of diltiazem or other potent inhibitors of CYP3A with simvastatin should be avoided, or close clinical monitoring should be used.

Pharmacology of diuretics.

The diuretics in our therapeutic armamentarium have predictable effects based on their nephron sites of action. All but spironolactone must reach the lumen or urinary side of the nephron to exert their effects. Thus, in settings of decreased renal function, doses must be increased to deliver more diuretic into the urine. In other edematous disorders, such as congestive heart failure (CHF) and cirrhosis, adequate amounts of diuretic reach the site of action if renal function is satisfactory. Diminished response in these conditions is caused by a decrease in the sensitivity of the nephron to the diuretic, the mechanism of which is unknown. Rather than using large single doses of diuretic in CHF and cirrhosis, multiple doses and/or combinations of diuretics should be used. Therefore, thiazide diuretics coupled with loop diuretics are most logical because they affect different nephron sites and the thiazide counteracts distal nephron hypertrophy that may occur with loop diuretics alone. Ample studies have shown that such combinations can result in a truly synergistic response. Using pharmacokinetics and pharmacodynamics of diuretics, we can design therapeutic regimens in which satisfactory control of fluid and electrolyte homeostasis can be achieved in the vast majority of patients.

Diuretic therapy in congestive heart failure.

Diuretics are a mainstay of therapy in patients with congestive heart failure. A small number of patients can achieve adequate diuresis with a thiazide diuretic alone, but most require a loop diuretic. Some patients with severe disease require combinations of diuretics. Most patients with congestive heart failure manifest resistance to diuretics by having a diminished natriuresis compared with healthy counterparts. This diminished response even to potent diuretics means that dietary sodium may exceed sodium excretion, resulting in patient decompensation. The pharmacokinetics and pharmacodynamics of loop diuretics have been characterized in patients with congestive heart failure, thereby allowing rational therapeutic strategies in terms of what type of doses should be administered, how often, and when to use diuretic combinations. The purpose of this review is to show how understanding pharmacokinetics and pharmacodynamics results in logical diuretic use. (c)2000 by CHF, Inc.

Use of diuretics in cirrhosis and nephrotic syndrome.

Patients with cirrhosis and with nephrotic syndrome have subnormal responses to diuretics. The mechanism of this effect in cirrhosis is decreased pharmacodynamics of response. Large doses of diuretic are not useful in this setting. Instead, more frequent administration of modest doses is required. In nephrotic syndrome, substantial amounts of diuretic are rendered inactive by binding to urinary albumin, thereby mandating larger doses. In addition, the pharmacodynamics of response are altered so that doses must be administered more frequently. Rarely, patients may benefit from combinations of albumin and a loop diuretic.

Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end-stage renal disease: evidence for a 'futile cycle' of elimination.

AIMS: To assess if futile cycling of ketoprofen occurs in patients with decreased renal function. METHODS: Ketoprofen was administered to six haemodialysis-dependent patients with end-stage renal disease as single (50 mg) or multiple doses (50 mg three times daily, for 7 days). Plasma and dialysate concentrations of the unconjugated and glucuronidated R- and S-enantiomers of ketoprofen were determined using h.p.l.c. following the single and multiple dosing. RESULTS: The oral clearance was decreased and terminal elimination half-lives of R- and S-ketoprofen and the corresponding acyl glucuronides were increased in functionally anephric patients compared with healthy subjects. In contrast with the R-isomers, S-ketoprofen and S-ketoprofen glucuronide exhibited an unexpected accumulation (2.7-3. 8 fold) after repeated dosing achieving S:R ratios of 3.3+/-1.7 and 11.2+/-5.3, respectively. The plasma dialysis clearances for R- and S-ketoprofen glucuronides were 49.4+/-19.8 and 39.0+/-15.9 ml min-1, respectively, and 10.8+/-17.6 and 13.3+/-23.5 ml min-1 for unconjugated R- and S-ketoprofen. CONCLUSIONS: The selective accumulation of S-ketoprofen and its acyl glucuronide are consistent with amplification of chiral inversion subsequent to futile cycling between R-ketoprofen and R-ketoprofen glucuronide. Severe renal insufficiency, and possibly more modest decrements, results in a disproportionate increase in systemic exposure to the S-enantiomer which inhibits both pathologic and homeostatic prostaglandin synthesis.