Sodium-ion storage properties of nickel sulfide hollow nanospheres/reduced graphene oxide composite powders prepared by a spray drying process and the nanoscale Kirkendall effect.

Spray-drying and the nanoscale Kirkendall diffusion process are used to prepare nickel sulfide hollow nanospheres/reduced graphene oxide (rGO) composite powders with excellent Na-ion storage properties. Metallic Ni nanopowder-decorated rGO powders, formed as intermediate products, are transformed into composite powders of nickel sulfide hollow nanospheres/rGO with mixed crystal structures of Ni3S2 and Ni9S8 phases by the sulfidation process under H2S gas. Nickel sulfide/rGO composite powders with the main crystal structure of Ni3S2 are also prepared as comparison samples by the direct sulfidation of nickel acetate-graphene oxide (GO) composite powders obtained by spray-drying. In electrochemical properties, the discharge capacities at the 150(th) cycle of the nickel sulfide/rGO composite powders prepared by sulfidation of the Ni/rGO composite and nickel acetate/GO composite powders at a current density of 0.3 A g(-1) are 449 and 363 mA h g(-1), respectively; their capacity retentions, calculated from the tenth cycle, are 100 and 87%. The nickel sulfide hollow nanospheres/rGO composite powders possess structural stability over repeated Na-ion insertion and extraction processes, and also show excellent rate performance for Na-ion storage.

Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin.

OBJECTIVE: To determine the safety and efficacy of the long-acting analog insulin glargine compared with NPH insulin in patients with type 2 diabetes who were previously treated with insulin alone. RESEARCH DESIGN AND METHODS: A total of 518 subjects with type 2 diabetes who were receiving NPH insulin with or without regular insulin for postprandial control were randomized to receive insulin glargine (HOE 901) once daily (n = 259) or NPH insulin once or twice daily in = 259) for 28 weeks in an open-label, multicenter trial. Doses were adjusted to obtain target fasting glucose <6.7 mmol/l. At study end point, the median total daily insulin dose in both treatment groups was 0.75 IU/kg. RESULTS: The treatment groups showed similar improvements in HbA1c from baseline to end point on intent-to-treat analysis. The mean change (means +/- SD) in HbA1c from baseline to end point was similar in the insulin glargine group (-0.41 +/- 0.1%) and the NPH group (-0.59 +/- 0.1%) after patients began with an average baseline HbA1c of approximately 8.5%. The treatments were associated with similar reductions in fasting glucose levels. Overall, mild symptomatic hypoglycemia was similar in insulin glargine subjects (61.4%) and NPH insulin subjects (66.%) However, nocturnal hypoglycemia in the insulin glargine group was reduced by 25% during the treatment period after the dose-titration phase(26.5 vs. 35.5%, P = 0.0136). Subjects in the insulin glargine group experienced less weight gain than those in the NPH group (0.4 vs. 1.4 kg, P < 0.0007). CONCLUSIONS: In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once- or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine deonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin.

The use of confidence intervals to describe the precision of trough/peak ratios for diltiazem CD in the treatment of hypertension.

Once-daily diltiazem hydrochloride, CARDIZEM CD (diltiazem CD) 300 mg, was evaluated for safety, efficacy, and the relationship between peak and trough antihypertensive effects in a multicenter, placebo-controlled, parallel design trial. After a 4- to 6-week placebo baseline period, 111 patients with essential hypertension were randomized to receive placebo or diltiazem CD for a 4-week treatment period. Diltiazem CD 300 mg lowered supine diastolic and systolic blood pressure at trough significantly more than placebo (-7.5 mm Hg vs. -1.3 mm Hg, P = 0.0001 and -6.4 mm Hg vs. 0.5 mm Hg, P = 0.0051, respectively). Supine blood pressure was also measured hourly from 6 to 10 hours after the dose to assess peak effect and trough/peak ratios. Using the largest residual drug effect of -8.3 mm Hg at 6 hours as peak and the 24-hour residual drug effect of -5.9 mm Hg as trough, the trough/peak ratio was estimated to be 71%, with a lower one-sided 95% confidence limit of 50%. The precision of the trough/peak ratio is estimated by the lower confidence limit of 50%, which establishes the trough/peak ratio as statistically > or = 50%. No statistically significant differences in supine DBP were noted between the peak effect hours, indicating a plateau of the peak antihypertensive effect from 6 to 10 hours postdose. Diltiazem CD therapy was well tolerated, with no serious treatment-related adverse events reported during the trial and no patients discontinuing the trial due to a treatment-related adverse event.(ABSTRACT TRUNCATED AT 250 WORDS)

24-hour efficacy of once-daily diltiazem in essential hypertension.

The safety and effectiveness of a once daily formulation of diltiazem hydrochloride (diltiazem CD) in the treatment of essential hypertension was assessed in a total of 127 patients with supine diastolic blood pressures (DBP) of 95 to 110 mmHg randomized to diltiazem CD (n = 61) or placebo (n = 66). Patients were titrated to doses of 120, 240, or 360 mg to achieve DBP reduction to less than 90 mmHg. At end study diltiazem CD changed trough supine SBP and DBP by -8.4 +/- 1.7 (p = 0.0009) and -8.6 +/- 1.1 mmHg (p = 0.0075), respectively. Heart rate was not significantly changed (-1.3 +/- 1.1 beats/min, p = 0.4362). The average dose of diltiazem CD was 268 mg with 69% achieving a clinical response. A subset of 47 patients underwent ambulatory blood pressure monitoring to assess the consistency of the effect over the full 24-h dosing interval. Diltiazem CD lowered DBP and SBP throughout the dosing interval. The overall side effect profile was similar to placebo. This study provides evidence of 24-h efficacy of this new, once daily formulation of diltiazem.

A dose-response trial of once-daily diltiazem.

This trial was performed to determine the safe and effective dosage range of once daily diltiazem (diltiazem CD) capsules for treatment of essential hypertension. Patients with essential hypertension having supine diastolic blood pressure values greater than or equal to 95 mm Hg and less than or equal to 110 mm Hg were randomly assigned to receive placebo or one of four doses of diltiazem CD: 90, 180, 360, or 540 mg. Blood pressure was measured at trough, 24 hours after the dose, and at the time of peak effect, 10 hours after the dose. Diltiazem CD lowered both supine diastolic and systolic blood pressure. A linear dose response was seen with changes in diastolic and systolic blood pressure and heart rate for trough and peak measurements. Trough/peak ratios for the 180, 360, and 540 mg doses were all greater than 0.50. Adverse effects were dose related; those most commonly reported were headache (8.6%), bradycardia (8.1%), and edema (7%), with bradycardia and edema possibly dose related. It is therefore concluded that diltiazem CD is a safe and effective antihypertensive agent.

The determinants of response to diltiazem in hypertension.

We examined factors (blood pressure, plasma renin activity, and age) influencing the antihypertensive response in essential hypertensive patients given 240 mg/day of slow-release diltiazem in an unblinded study after a placebo run-in period. Subjects provided a range of diastolic blood pressures (90 to 115 mm Hg), of age (31 to 70 years), and of plasma renin activity (0.1 to 2.7 ng angiotensin I/ml/hr) on a 70 to 150 mEq sodium diet. Blood pressure, plasma renin activity, and plasma diltiazem concentrations were measured after the first (n = 21) and final dose (n = 19) of 120 mg diltiazem, twice daily for 4 weeks. Multiple linear stepwise regression of change in blood pressure versus age, plasma renin activity, and baseline blood pressure showed baseline blood pressure was the only predictor of response (p = 0.0002). For each increase of 10 mm Hg in baseline pressure there was a 7 mm Hg greater decrease in diastolic blood pressure. We conclude that patient age and plasma renin activity are not clinically significant predictors of antihypertensive response to diltiazem in hypertension.

A randomized controlled trial of the effects of three antihypertensive agents on blood pressure control and quality of life in older women.

We conducted a multicenter, randomized, double-blind, parallel group trial to compare the impact of titrated doses of atenolol (50 to 100 mg once a day), enalapril (5 to 20 mg once a day), and diltiazem (sustained release) (60 to 180 mg twice a day) on blood pressure and quality of life in older hypertensive women. Two hundred forty-two patients were randomized. Dose titration was completed by week 4 after randomization, and the maintenance phase was completed at week 16. Diltiazem (sustained release) demonstrated greater diastolic blood pressure lowering at both weeks 8 and 16 by an intent-to-treat analysis. At week 16, diltiazem changed diastolic blood pressure -13.7 +/- 0.7 mm Hg compared with -10.8 +/- 1.1 mm Hg for atenolol, and -10.5 +/- 0.9 mm Hg for enalapril. Diltiazem also demonstrated greater lowering of systolic blood pressure at week 3, but these differences in systolic blood pressure had decreased by week 16. More patients were classified as treatment failures during the 16 weeks of the trial for atenolol (15%) than for diltiazem (2.5%), while the treatment failure rate was intermediate with enalapril (8%). Total rates of adverse events were equivalent across the three treatment arms. There were few significant differences in the impact of the three treatments on mean scores of quality-of-life measures at week 16. There was a trend for atenolol to have somewhat worse quality-of-life scores, but none of these differences were statistically significant. In conclusion, all three treatment regimens were effective in lowering diastolic blood pressure without significant differences in rates of adverse events or deleterious effects on quality of life.

The intrauterine probe electrode.

An intrauterine probe electrode was inserted into 100 laboring women and 366 bipolar electrode combinations were tested. A noise-cancelling technique was used with the final 28 subjects to remove competing maternal cardiac signals. Twenty-four (86%) had fetal heart rate tracings with sufficient technical quality to allow determination of the baseline fetal heart rate.

Effect of dietary protein on renal tubular clearance of drugs in humans.

Diet is one of many factors that influence the pharmacokinetics of drugs. The level of protein intake has been found to significantly influence drug metabolism and glomerular filtration, both of which play an important role in the clearance of drugs. Recently, a marked change, resulting from restricted dietary protein intake, has been reported in the handling of several drugs which are reabsorbed and/or secreted by the renal tubules. In studies of healthy volunteers on protein-restricted diets the renal clearance and fractional excretion of model compounds have been altered, falling to 30% of values obtained on normal diets in the case of the weak acids oxipurinol and uric acid; the fractional excretion of the weak base cimetidine has been increased by 30%. These studies have also found that the change in the renal clearance of both acids is sustained with prolonged dietary protein-calorie restriction, and that, for oxipurinol, the magnitude of the change is directly related to the quantity of protein in the diet, the change is related specifically to the protein content in the diet (and not the total calories), the onset of change is rapid, and on a low-protein diet the renal clearance undergoes marked diurnal variation. The mechanism for the alteration in tubular function is not clear, but may be related to renal haemodynamic changes or competition for transport associated with protein intake. Regardless of the mechanism, these results have important implications for pharmacokinetic research and clinical practice.

Reduced renal clearance of oxypurinol during a 400 calorie protein-free diet.

A decrease in dietary protein intake lowers the clearance of a number of substances excreted principally by the kidney including uric acid and oxypurinol, the major metabolite of allopurinol. We studied the kinetics of uric acid and oxypurinol in seven healthy volunteers on a normal protein diet (2600 calories; 100 g protein) followed by a 400 calorie, protein-free diet. A 600 mg dose of allopurinol was given orally after 6 days of the normal protein diet and again after 2 days of the 400 calorie, protein-free diet. Two major findings emerged: first, the renal clearance of oxypurinol was reduced from 21.2 +/- 1.9 ml/min during the normal protein diet to 12.3 +/- 1.2 ml/min (P less than .05) during the 400 calorie, protein-free diet, and second, there was a striking diurnal difference in oxypurinol renal clearance with a 41% decrease in the oxypurinol clearance at night (8 PM to 8 AM) versus day (8 AM to 8 PM) on the 400 calorie, protein-free diet.

Renal clearances of oxypurinol and inulin on an isocaloric, low-protein diet.

In previous studies a low-calorie, low-protein diet caused a sustained reduction in both oxypurinol and uric acid renal clearances (CLR). With the hypothesis that the decrease in CLR was due to the low-protein and not the low-caloric content of the diet, we studied the CLR of oxypurinol, uric acid, creatinine, and inulin in normal subjects during isocaloric (2600 calories per 70 kg per day), normal-protein (150 gm per day), and low-protein (19 gm per day) diets. There were three major findings: (1) the CLR of oxypurinol declined from 26.6 +/- 1.8 ml/min on the normal-protein diet to 13.5 +/- 1.4 ml/min on the isocaloric low-protein diet (p less than 0.05); (2) the CLR of inulin and creatinine fell 14% and 20%, respectively, on the low-protein diet compared with the normal-protein diet (both p less than 0.05); and (3) there was a diurnal variation in the CLR of oxypurinol. We conclude that the decreased CLR of oxypurinol was the result of the reduced protein content of the diet and the CLR of both inulin and creatinine were decreased on the low-protein diet.

Superactivated charcoal versus cholestyramine for cholesterol lowering: a randomized cross-over trial.

To evaluate the relative abilities of superactivated charcoal (20 g twice daily) and cholestyramine (8 g twice daily) to lower plasma cholesterol concentrations acutely, six hypercholesterolemic patients were studied using a randomized cross-over design. After a 1-week dietary control period, each subject received 3 weeks of each treatment regimen on separate occasions. Superactivated charcoal and cholestyramine reduced total plasma cholesterol by 21.8 +/- 3.8% and 16.2 +/- 2.4%, respectively. Side effects were mild and similar for both treatments. At the dosage regimens studied, superactivated charcoal and cholestyramine have comparable ability to lower plasma cholesterol concentrations.

Systolic blood pressure response in three subgroups of hypertensives treated with sustained-release diltiazem.

Data from a long-term, open-label diltiazem trial were analyzed to test the hypothesis that the magnitude of systolic blood pressure (SBP) response to diltiazem is dependent on pretreatment levels. The study design included a 2- to 4-week placebo period to establish stable qualifying pressures. Patients devoid of significant coexisting diseases with diastolic blood pressures (DBPs) greater than or equal to 95 mm Hg or SBPs greater than or equal to 160 mm Hg were titrated on sustained-release diltiazem (60-180 mg b.i.d.) over 2-6 weeks. Titration goals were greater than or equal to 10% drop in DBP or greater than or equal to 15% in SBP. Patients were followed up to 20 months. Based on pretreatment blood pressure, patients were divided into three subgroups: isolated systolic hypertension (ISH) (SBP/DBP; greater than or equal to 160/less than 95 mm Hg), isolated diastolic hypertension (IDH) (less than 160/greater than or equal to 95 mm Hg), and combined systolic and diastolic hypertension (CSDH) (greater than or equal to 160/ greater than or equal to 95 mm Hg). SBP changed significantly from baseline for all three groups. However, the percent reduction in SBP was significantly greater for patients with baseline SBP greater than or equal to 160 mm Hg when compared with patients with baseline SBP less than 160 mm Hg (-10.3 +/- 0.7% vs. -4.4 +/- 0.6%). In comparing the ISH and CSDH patient groups, the CSDH group required a larger diltiazem dose to achieve a SBP response similar to the ISH group. Diltiazem was well tolerated with only a 5% dropout due to adverse effects of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Digoxin toxicity in patients with high serum digoxin concentrations.

A retrospective study of the clinical course and outcome of patients with serum digoxin concentrations (SDCs) greater than 3 ng/mL was conducted to determine the probability of a patient without initial signs or symptoms of digoxin toxicity subsequently developing signs or symptoms. Of 123 patients with SDCs greater than 3 ng/mL, 54 had no apparent signs or symptoms of toxicity at the time the index SDC was determined (group 1). Of these 54, two patients developed definite digoxin toxicity, although neither suffered significant morbidity. Digoxin administration was reduced or discontinued in all patients but one in group 1. There were no significant differences between the patients who had no signs or symptoms of digoxin toxicity (group 1) and those who did have signs or symptoms (group 2) in the mean SDC (3.9 +/- 0.1 vs 4.2 +/- 0.2 ng/mL, respectively), the serum creatinine (2.9 +/- 0.2 vs 3.4 +/- 0.4 mg/dL), or the incidence of atrial fibrillation (29/54 vs. 35/69) and coronary artery disease (21/54 vs. 18/69). The authors conclude that clinically stable patients receiving digoxin who have elevated SDCs but are without signs or symptoms of digoxin toxicity are at low risk of developing serious digoxin toxicity and do not generally require treatment beyond the discontinuation of digoxin therapy.

The effect of dietary protein-calorie restriction on the renal elimination of cimetidine.

The renal elimination of the weak-base cimetidine was studied in five healthy male subjects during normal and restricted (low-protein, low-calorie) diets in a randomized crossover fashion. An intravenous dose of cimetidine, 7 mg/kg, was administered on day 7 of the normal (100 gm/70 kg protein/day) and the restricted (19 gm/70 kg protein/day) diets. The renal clearance of cimetidine was unchanged by the dietary restriction; however, the fractional excretion of cimetidine increased from 3.06 to 3.94 (P less than 0.05), indicating an apparent increase in net tubular secretion of cimetidine during the restricted diet. We conclude that cimetidine dosage adjustments are apparently not necessary for patients with acutely restricted nutrient intake, although other weakly acidic and basic drugs may require dosage changes.

Clinical pharmacology and therapeutics education for senior medical students.

In many medical schools instruction of students in clinical pharmacology remains informal and may be inadequate. To determine the short-term efficacy of a mandatory senior medical year course in clinical pharmacology, we compared examination scores of senior students in the College of Medicine, University of Iowa, either prior to or following the Clinical Pharmacology and Therapeutics Lecture Series. A significantly higher (P less than .001) mean score was demonstrated by students taking the examination following the course (75 +/- 4% correct) versus those taking the examination prior to the course (55 +/- 4% correct). To determine student acceptance, postcourse questionnaires were completed. Students surveyed immediately postcourse and alumni surveyed up to four years after graduation highly recommended the course and favored retaining it as a mandatory part of the fourth-year curriculum. This study confirms the efficacy and acceptance of senior medical courses in therapeutics and suggests an effective role for clinical pharmacologists in their design and execution.

Sustained reductions in oxipurinol renal clearance during a restricted diet.

The renal clearance of oxipurinol, the major metabolite of allopurinol, was studied in six healthy subjects during normal and restricted (low protein and low calorie) diets. A 600 mg oral dose of allopurinol was administered after 7 days of a normal diet (100 mg protein/day) and again after 2 and 4 weeks of a restricted diet (19 gm protein/day). The renal clearance of oxipurinol was reduced from 19.6 +/- 1.5 ml/min during the normal diet to 10.9 +/- 0.8 and 12.0 +/- 0.9 ml/min (both P less than 0.001) during the restricted diet at 2 and 4 weeks, respectively. These changes in oxipurinol renal clearance paralleled changes in uric acid renal clearance. Furthermore, the plasma oxipurinol half-life was increased from 27.0 +/- 1.7 hours during the normal diet to 51.1 +/- 4.3 and 45.7 +/- 3.7 hours (both P less than 0.001) during the restricted diet at 2 and 4 weeks, respectively. We conclude that dietary protein and calorie restriction cause a sustained reduction in the elimination of oxipurinol.