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Biomedical subjects

R E Cutler

Publications and source records attributed to R E Cutler.

At least 37 records · Page 2Linked to original sources
PubMed1990

Apparent reduced absorption of gemfibrozil when given with colestipol.

Colestipol and gemfibrozil may be used in combination to lower serum cholesterol and triglycerides. Since colestipol is known to bind certain anionic drugs, we studied the effect of colestipol on the pharmacokinetics of gemfibrozil in 10 patients with elevated serum cholesterol and triglycerides. Each patient received 600 mg of gemfibrozil by mouth during four different studies. Gemfibrozil was given randomly either alone, with, 2 hours before, or 2 hours after 5 grams of colestipol. The serum gemfibrozil concentration time curves were similar when gemfibrozil was given alone or two hours before or after colestipol. There was also no statistical difference in peak gemfibrozil concentration (Cmax), time to Cmax (tmax), area under the curve (AUC), or serum elimination half-life (t1/2) between any of these three treatments. However, when colestipol was given with gemfibrozil, there was a decrease in AUC (43.6 +/- 21.9 mg*hr/L) compared with gemfibrozil given alone (62.6 +/- 10.3 mg*hr/L) which was statistically different by both ANOVA and paired t-test. This finding suggests a decrease in gemfibrozil bioavailability. Cmax when colestipol was given with gemfibrozil (14.7 +/- 6.6 mg/L) was not statistically different from gemfibrozil alone (20.1 +/- 4.9 mg/L). However, the mean serum concentrations when gemfibrozil was given with colestipol were significantly lower at the 0.5, 1.0 and 1.5 hour sampling times when compared to the other regimens. Gemfibrozil serum elimination half-life was not significantly altered by combination with colestipol. The data suggest a reduction of gemfibrozil bioavailability when colestipol is administered concomitantly. Separating the administration of these two drugs by at least two hours will avoid this drug interaction.

Aged↗
PubMed1990

Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients.

This study was done to determine if the pharmacokinetics and gastric pH response of intravenous cimetidine are superior to oral dosing in seriously ill patients. A paired study of intravenous followed by oral liquid cimetidine was given to eight men and two women who were inpatients in a VA Hospital. Treatment was prescribed for either upper gastrointestinal (GI) bleeding or prophylaxis against GI bleeding. All patients received cimetidine 300 mg every 6 hours intravenously on day 1 and orally on day 2. After the fourth dose each day, venous blood samples and gastric pH measurements were taken serially for 6 hours. Peak serum cimetidine concentration was 2.0 +/- 0.5 mg/L for the intravenous dose and 1.5 +/- 0.3 mg/L for the oral dose (P = .001). Area under the curve (AUC) of cimetidine concentration was 3.81 +/- 1.1 mg/hr/L for the intravenous dose and 4.19 +/- 1.22 mg/hr/L for the oral dose (P greater than .30). Bioavailability (AUCpo/AUCiv) was 1.13 +/- 0.25, demonstrating complete oral absorption. The time during a 6-hour dosing interval that the gastric pH remained above 3.0 was 3.3 +/- 2.1 hours for the intravenous dose and 2.5 +/- 2.3 hours for the oral dose, P = .171). The time that the serum cimetidine concentration remained above 0.5 mg/L was 2.0 +/- 0.9 hours for the intravenous dose and 2.7 +/- 1.0 hours for the oral dose (P = .055). We concluded that bioavailability, time that gastric pH is maintained greater 3.0, and time that the serum cimetidine concentration is greater than 0.5 mg/L for intravenous cimetidine are not significantly different from oral cimetidine in seriously ill patients.

Administration, Oral↗
PubMed1990

Single-dose effects of ibopamine hydrochloride on renal function in patients with congestive heart failure.

To examine the renal effects of ibopamine HCl we evaluated 15 patients with New York Heart Association Class II-III congestive heart failure and mild renal insufficiency (creatinine clearance [CLcr] = 45-85 ml min-1). Diuretics and vasodilators were withheld and a sodium (Na+)-restricted diet was initiated. All patients exhibited positive Na+ balance at the time of evaluation. Hourly urine volumes, urine chemistries, serum chemistries, PAH and inulin/iothalamate clearances were determined 2 h pre and 4 h post a single 200 mg oral dose of ibopamine. Effective renal plasma flow, creatinine clearance, filtration fraction, and the fractional excretion of sodium and potassium were not significantly altered postdose. A significant increase in urine output and decrease in urine osmolality were seen at all time points postdose. A significant reduction in serum potassium (2 and 3 h) and blood urea nitrogen (1, 3 and 4 h) concentrations occurred. Measurements of glomerular filtration rate by inulin or [125I]-iothalamate produced differing results in the patient groups studied. We conclude that a single dose of ibopamine does not produce significant improvements in renal function in patients with congestive heart failure, mild renal insufficiency and positive sodium balance.

Acute Kidney Injury↗
PubMed1989

Modulation of soluble ovarian adenosine 3',5'-monophosphate-dependent protein kinase activity during prepubertal development in the rat. II. Evaluation of the catalytic subunit inhibitor activity.

In a previous report on the ontogeny of the ovarian adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase activity during prepubertal development of the rat, we concluded that the 4-fold decline in cAMP-dependent protein kinase activity observed in ovaries of 21- to 23-day-old rats was due to the presence of a heat-labile inhibitor in the ovarian extracts (Hunzicker-Dunn et al., 1984). We developed an assay for this ovarian kinase inhibitor activity that was based on the observation that ovarian cytosol added to an exogenous catalytic subunit of cAMP-dependent protein kinase caused a time-dependent and ovarian cytosol protein concentration-dependent inhibition of exogenous catalytic subunit phosphotransferase activity. The present studies were conducted to evaluate the basis for this catalytic subunit inhibitor present in soluble rat ovarian extracts of prepubertal-aged rats. This inhibitor activity was absent from cytosol extracts of rat corpora lutea, rat liver, rabbit follicles, and rabbit corpora lutea. Inhibitor activity present in rat ovarian cytosol was not attributable to insufficient levels of the phosphorylation substrate Kemptide. Inhibitor activity was also not related to the presence of the large amount of catalytic subunit-free regulatory subunit of the cAMP-dependent protein kinase present in ovarian extracts of late juvenile-aged rats. Inhibitor activity, however, did correlate with an endogenous adenosine triphosphatase (ATPase) activity that reduced assay ATP concentrations below levels needed to accurately measure phosphotransferase activity, despite the presence of sodium fluoride (an ATPase inhibitor) and ATP concentrations 5- to 15-fold greater than the Km of the kinase for ATP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1988

Oral flecainide pharmacokinetics in patients with impaired renal function.

The pharmacokinetics of flecainide acetate were studied in 20 patients with varying degrees of renal impairment following a single oral dose. The patients were divided into two groups, on the basis of renal creatinine clearance (CLCR), for statistical and kinetic analysis. Patients with a CLCR between 4 and 41 mL/min/m2 were designated group 1 and those below 4 mL/min/m2 or unmeasurable because of lack of urine output were designated group 2. In both groups peak plasma flecainide concentrations, time to peak concentrations, and apparent volume of distribution (Vd) were similar to those reported in healthy subjects with normal renal function. The mean flecainide plasma elimination half-lives from both groups 1 and 2 were longer than those previously reported by several investigators in normal subjects. Nine patients in group 1 and seven patients in group 2 had half-lives within the range reported in healthy subjects. Therefore, CLCR alone is not a good predictor of plasma elimination half-life following a single oral dose of flecainide. Although renal clearance of flecainide is significantly reduced in end-stage renal disease (ESRD), total plasma clearance of flecainide (CLflec) was not reduced to the same degree, although there was a significant, modest correlation with CLCR. Less than 1% of the administered oral dose of flecainide was removed during hemodialysis. The relationship between dosage and plasma elimination half-life in patients with ESRD needs further study to evaluate possible dose-dependent kinetics.

Administration, Oral↗
PubMed1988

Flecainide pharmacokinetics after multiple dosing in patients with impaired renal function.

STUDY OBJECTIVE: To determine the pharmacokinetics of oral flecainide acetate after single and multiple doses in patients with impaired renal function. DESIGN: Paired study of single followed by multiple oral doses. SETTING: PATIENTS enrolled in a Veterans Administration Hospital renal subspecialty clinic and dialysis unit. PATIENTS: Twenty men and one woman between the ages of 33 and 74 years with impaired renal function including ten patients with end-stage renal disease receiving maintenance hemodialysis. INTERVENTIONS: All patients received a single, oral, 200-mg dose of flecainide acetate followed by sequential venous blood sampling. Seven to 14 days after the single-dose study, each patient received 100 mg of flecainide acetate by mouth every 12 hours or every 24 hours for 10 days. Venous blood samples were drawn periodically during multiple dosing and sequentially after the last dose. Measurements and primary results: Peak flecainide acetate concentrations (micrograms/L) were 330 +/- 104 micrograms/L (mean +/- SD) after the single dose and 687 +/- 505 micrograms/L after multiple doses. Time to peak occurred at 3.3 +/- 2.3 hours and 2.7 +/- 1.2 hours after single and multiple doses, respectively. The apparent volume of distribution was 8.2 +/- 2.9 L/kg and 9.2 +/- 5 L/kg after single and multiple dose studies, respectively. Plasma elimination half-life after the single dose (20.4 +/- 9.0 hours) was significantly shorter (P less than .001) than after multiple doses (37.8 +/- 39.7 hours), as was total body clearance: 391 +/- 154 mL/min versus 302 +/- 194 mL/min. There were no statistically significant differences between pharmacokinetic measurements determined for patients on chronic hemodialysis when compared with nondialysis patients during the multiple-dose study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Pharmacokinetics of iothalamate in endstage renal disease.

Some nephrologists make alterations in routine peritoneal and hemodialysis schedules after diagnostic studies that use radiographic contrast agents. A study to determine the pharmacokinetics of one contrast agent, iothalamate, is reported. The plasma (total body) clearance of iothalamate was measured in seven patients who had endstage renal disease (ESRD) and who received maintenance hemodialysis. During an interdialytic period, plasma clearance of iothalamate varied from 0.7 to 5.2 mL/min (3.1 +/- 1.8 mL/min, mean +/- SD) with an elimination rate constant (beta) of 0.0164 +/- 0.01 hr-1, a terminal half-life of 61 +/- 42 hours, and an estimated distribution volume of 11 +/- 3.9 L. Hemodialysis clearance of iothalamate was 104 +/- 54 mL/min. With the assumption that iothalamate is mainly distributed in the extracellular fluid (ECF) compartment, the theoretical fluid shift from the intracellular fluid (ICF) compartment to the ECF compartment was 323 mL after administration of the largest dose (2.1 mL/kg or 1.6 mmol/kg of body weight) of 60% meglumine iothalamate solution. The average maximum serum osmolarity change was less than expected, suggesting some type of internal buffering of meglumine iothalamate. In the first few hours after radiocontrast administration in four patients, the average change in serum osmolarity was 5 mmol/L; the average change in serum sodium concentration during this same time was a decrease of 0.5 mmol/L. The minor increase in ECF volume induced by hyperosmolar contrast agents does not require immediate dialysis in most patients. When needed, however, for contrast-related adverse effects, hemodialysis is efficient in rapidly removing iothalamate.

Aged↗
PubMed1988

The effects of renal function on the disposition of isradipine.

The effect of renal function on isradipine kinetics was examined in four groups of subjects (N = 55) who had normal or impaired renal function. Each subject received isradipine orally as a 10-mg capsule. Serial blood samples were obtained from 0 to 48 hours postdose and the isradipine plasma concentrations determined by radioimmunoassay. Kinetic parameters, Cmax, lambda 3, t 1/2, AUC, CL'o (oral clearance), and CLo (oral clearance standardized to body weight) were determined. Marked intersubject variability of the pharmacokinetic parameters was observed. No statistically significant differences (P greater than .05) were found for AUC, Cl'o, and Clo parameters when renal impairment groups were compared with controls. AUC values were lower (P less than .05), however, for the group with severe renal function impairment than for groups with mild or moderate renal function impairment. No significant correlations (r = -.23, P greater than .05; and r = .13, P greater than .05, respectively) were found between creatinine clearance (CLCR) and CLo and between age and CLo. Considering the interpatient variability in isradipine disposition and the lack of significant differences in CLo between groups, no clear-cut dosing regimen alterations, based on single-dose data, are warranted in renal impairment.

Adult↗
PubMed1988

Use of APACHE II classification to evaluate outcome of patients receiving hemodialysis in an intensive care unit.

We retrospectively reviewed the medical records of all patients who were admitted to the medical and surgical intensive care units of a university center (N = 100) and its affiliated veterans' hospital (N = 46) between 1982 and 1986 to receive dialysis. The APACHE II severity-of-disease classification was used to identify the cases in which the prognosis was so poor that no long-term benefit would accrue from hemodialysis treatment. A "risk of death" was calculated for each patient. At a risk of death of 70% or greater, the system correctly predicted the demise of patients with 100% specificity regardless of what interventions were carried out. Sensitivity and predicted negative value were low in all cases, however, indicating a poor predictability of those who will survive. Withholding the average of 6 dialysis treatments that this group of patients received would probably have reduced patient suffering during a lingering terminal illness and led to a savings of about $4,500 per patient.

Adult↗
PubMed1987

Antihypertensive therapy in the elderly. Effects on blood pressure and cerebral blood flow.

Antihypertensive therapy significantly reduces cardiovascular morbidity and mortality in the rapidly growing population of elderly patients. However, the desire to treat more of these patients is dampened by the concern that a reduction in blood pressure may compromise cerebral blood flow, causing untoward consequences. This study evaluated the therapeutic effect of titrated doses of prazosin, an alpha-adrenergic blocking agent, on systemic blood pressure and cerebral blood flow in elderly patients with chronic stable hypertension. Prazosin alone or co-administered with hydrochlorothiazide significantly lowered mean systolic and diastolic blood pressures in 31 elderly hypertensive patients. At the same time, however, there was no significant change in cerebral blood flow, which was measured in eight patients. Neither harmful biochemical changes nor treatment-related adverse effects were observed in any patients. Prazosin therapy alone or in combination with low-dose diuretic therapy was effective in the treatment of hypertension in this elderly population. Furthermore, blood pressure reduction with prazosin therapy was accomplished without compromising cerebral blood flow and without unfavorably altering lipid profiles.

Aged↗
PubMed1987

The effect of renal function on the pharmacokinetics of gemfibrozil.

STUDY OBJECTIVE: to determine the effect of renal function on the pharmacokinetics of gemfibrozil following single and multiple oral doses. DESIGN: nonrandomized; paired studies of single versus multiple doses. SETTING: patients enrolled in a veterans hospital renal subspecialty clinic. PATIENTS: 17 male patients 57 to 74 years old selected for various levels of renal function, including end-stage renal disease. INTERVENTIONS: patients initially received 600 mg of oral-gemfibrozil followed by sequential venous blood sampling. Seven to 14 days later, the patients started receiving gemfibrozil, 600 mg bid. Venous blood samples were obtained over the following 10 days and frequently during a 24-hour washout phase. MEASUREMENTS AND MAIN RESULTS: peak gemfibrozil concentrations (mg/L) were 11.1 (3.9 SD) for the single dose and 10.2 (3.8) for the multiple-dose study. Time to peak concentration (hr) was 2.1 (1.0) and 1.8 (0.6), respectively. The mean half-life of elimination (hr) from the single-dose study was 6.4 (11.8) compared with the multidose study of 3.0 (3.1), which did not reach statistical significance (P = .25). The difference between the area under the curve for the single versus the multiple-dose study approached statistical significance (P = .054). The coefficient of determination for creatinine renal clearance versus the plasma clearance of oral gemfibrozil was 0.009 (P = .72) for the single-dose regimen and 0.331 (P = .016) for the multiple-dose study. CONCLUSION: the half-life of gemfibrozil is independent of renal function for both single- and multiple-dose regimens. Dosing schedules do not require alteration for renal insufficiency.

Aged↗
PubMed1987

Effects of a magnesium-free dialysate on magnesium metabolism during continuous ambulatory peritoneal dialysis.

While the use of magnesium-containing compounds is usually contraindicated in dialysis patients, the risk of toxicity from hypermagnesemia can be reduced by lowering the magnesium concentration in dialysate. We examined the effects of a magnesium-free dialysate on both serum magnesium level and the peritoneal removal rate of magnesium over 12 weeks in 25 stable patients undergoing continuous ambulatory peritoneal dialysis (CAPD). After 2 weeks, the serum magnesium level decreased from 2.2 to 1.9 mg/dL (0.9 to 0.8 mmol/L) (P less than .02) and the peritoneal removal rate increased from 66 to 83 mg/d (2.8 to 3.5 mmol/d) (P less than .05), with both values remaining stable thereafter. There was a strong association between these parameters (r = -0.62, P less than .05), suggesting that the serum magnesium level decreased as a result of the initial increased peritoneal removal rate. For an additional 4-week period, a subgroup of nine patients received magnesium-containing, phosphate binding agents instead of those containing only aluminum. During this phase, serum inorganic phosphorus was well controlled. The serum magnesium level increased only from 1.8 to 2.5 mg/dL (0.7 to 1.0 mmol/L) (P less than .05), due in great part to the concomitant 41% rise in peritoneal magnesium removal from 91 to 128 mg/d (3.8 to 5.3 mmol/d) (P less than .05). No toxicity was noted during the entire 16-week study period, nor did serum calcium change. Thus, serum magnesium levels remained within an acceptable range as magnesium-containing phosphate binders were given through the use of magnesium-free peritoneal dialysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum Hydroxide↗
PubMed1985

Serum and dialysate concentrations of cephalexin following repeated dosing in CAPD patients.

Oral cephalexin, 1 to 2 g daily for 3 days, was given to six stable, noninfected patients receiving maintenance continuous ambulatory peritoneal dialysis (CAPD). The peak serum concentration after a 2 g initial dose was between 73 and 123 mg/L. On the second and third day in five patients who received a 2 g daily oral dose, the serum concentrations were between 35 and 118 mg/L in serum obtained 1 to 1.5 hours after the dosing. Similar serum concentrations were seen in one patient who only received a 1 g oral dose on the second and third day. Cephalexin concentrations in the peritoneal dialysate reached a peak on the first day between 4 to 14 hours after the dose and were between 31 to 78 mg/L. During the second and third day, the highest cephalexin concentration was 118 mg/L and the lowest was 12 mg/L. The data are consistent with the feasibility of oral cephalexin for treatment of CAPD-associated peritonitis with microorganisms that are sensitive to these levels of cephalexin.

Administration, Oral↗
PubMed1985

Radiocontrast-induced renal failure.

Review of the literature concerning contrast-induced renal dysfunction shows that the currently used agents are remarkably safe with careful patient selection. Clinically apparent kidney failure after their use is essentially nonexistent in those without preexistent renal insufficiency. The incidence rises rapidly in those with azotemia from any cause, however, and diabetic persons with nephropathy are perhaps at special risk. Vigorous volume expansion is possibly effective as a preventive measure and may attenuate adverse effects in those in whom postcontrast dysfunction occurs. New agents are becoming available. It is not yet known if these will prove safer or cost-effective. They have some experimentally demonstrated and theoretic advantages over the presently used agents.

Acute Kidney Injury↗