Results of the first U.S. double-blind, placebo-controlled, multicenter clinical study in asthma with pranlukast, a novel leukotriene receptor antagonist.

Pranlukast (SB 205312; ONO-1078), a potent, orally active selective cysteinyl-leukotriene receptor antagonist (LTRA), was developed in Japan for the treatment of asthma. This article reports results of the initial U.S. clinical evaluation of pranlukast. The primary objective of this multicenter study was to evaluate the safety and tolerability of pranlukast administered at doses of 337.5 mg b.i.d. and 450 mg b.i.d. in 65 patients with mild to moderate asthma. Pranlukast, a novel LTRA, is safe and well tolerated at doses of 337.5 mg b.i.d. and 450 mg b.i.d. Pranlukast has demonstrated clinical activity in patients with asthma.

A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma. Auranofin Multicenter Drug Trial.

BACKGROUND: Previous clinical studies have demonstrated that injectable gold salts and the oral gold compound, auranofin, possess significant steroid-sparing effects in the treatment of asthma. OBJECTIVES: The objectives of this investigation were to determine whether auranofin could reduce oral corticosteroid requirements and to evaluate the safety of auranofin in the treatment of chronic corticosteroid-dependent asthma. METHODS: Patients with asthma were eligible if they required at least 10 mg of prednisone per day for control and prevention of asthma exacerbations. Two hundred seventy-nine patients with chronic corticosteroid-dependent asthma (requiring > or = 10 mg/day) were randomized to receive auranofin, 3 mg twice daily, or placebo during an 8-month clinical trial, which was divided into three phases including: a 4-week baseline period (phase I), a 6-month double-blind treatment and steroid reduction period (phase II), and a 4-week posttreatment observation period during which steroid and auranofin doses or placebo doses were maintained at levels achieved by the end of phase II (phase III). The primary efficacy variable was "therapeutic success" or reduction of daily corticosteroid use by 50% or more. RESULTS: The proportion of patients in the auranofin group achieving therapeutic success (41%) was significantly higher than that in the placebo group (27%) (p = 0.01). This effect was greatest in patients requiring 10 to 19 mg of oral prednisone per day at baseline (p < 0.001). In all treated patients, including those who did and did not complete the trial, significant reduction (> or = 50% of baseline) in oral corticosteroid dosage was achieved in the auranofin group (60%) compared with the placebo group (32%) (p < 0.001). There were no significant differences between treatment groups in symptoms, concomitant medication use, or lung function. Mean serum total IgE levels decreased significantly from baseline in the auranofin group (-44.63 IU/ml) compared with the placebo group (p = 0.001). Gastrointestinal and cutaneous adverse events were greater in the auranofin group. CONCLUSIONS: Auranofin demonstrated a steroid-sparing effect without concomitant worsening of symptoms or lung function and appeared to be more effective in patients dependent on 10 to 19 mg of prednisone per day. Therefore this study has demonstrated that auranofin is useful as a steroid-sparing agent in the treatment of chronic corticosteroid-dependent asthma.

Intraoperative versus routine hemodialysis in end-stage renal disease patients undergoing open-heart surgery.

Of 13 chronic hemodialysis end-stage renal disease (ESRD) patients undergoing open-heart surgery, 7 received intraoperative hemodialysis (IHD) during cardiopulmonary bypass and 6 received hemodialysis on a routine basis (RHD). Within the groups, IHD patients had significantly lower post-operative mean serum potassium and mean plasma creatinine concentrations compared to mean preoperative values. Postoperative mean BUN tended to decrease and mean serum bicarbonate concentration was unchanged as compared to mean preoperative values. In the RHD group, however, post-operative mean serum potassium concentration tended to increase, mean serum bicarbonate concentration significantly declined and mean BUN was unchanged as compared to mean preoperative values. An average of 2.1 +/- 0.5 liters of fluid was removed from the IHD patients during cardiopulmonary bypass. Post-operatively, 0 of 7 IHD patients versus 4 of 6 RHD patients required parenteral sodium bicarbonate therapy (chi 2, p less than 0.01). On average, RHD patients required hemodialysis 1 day after surgery, whereas IHD patients were hemodialyzed 2 days after surgery (p = 0.009). We conclude that IHD lessened postoperative hyperkalemia and metabolic acidosis and delayed postoperative hemodialysis by an additional day. IHD should be considered as an adjunct to RHD therapy in the management of ESRD patients undergoing open-heart surgery.

Continuous intragastric delivery of fenoldopam: relationship between plasma concentration and effects on renal function.

1. The pharmacodynamics of the dopamine DA1 agonist fenoldopam were examined in six healthy male volunteers after constant intragastric infusions of fenoldopam at dosages of 0, 10, 25, 50 and 75 mg h-1 for 6 h. 2. Hourly p-aminohippurate (PAH) clearance was used to assess fenoldopam induced renal plasma flow changes. Marked dose-related increases in renal plasma flow were noted with a maximal increase of 65% over baseline values of 711 ml min-1 being seen at the 75 mg h-1 rate. No changes in sodium excretion and glomerular filtration rate were observed. 3. Mean steady-state fenoldopam plasma concentrations were related to mean PAH clearance based on an Emax model (r = 0.996) with an Emax of 1350 ml min-1 and an EC50 of 6.2 ng ml-1. 4. Mean steady-state plasma concentrations of fenoldopam-7-sulphate and fenoldopam-8-sulphate failed to increase with dose but were linearly correlated to mean PAH changes (r = 0.998, r = 0.981 respectively). 5. These results support the concept of extending fenoldopam's duration of action through the development of an oral sustained delivery system.

Selectivity of metoclopramide for endocrine versus renal effects of dopamine in normal humans.

The purpose of the present study was to evaluate the effect on renal function of dopamine (low dose, 2 micrograms/kg/min) inhibition by a low-dose infusion of metoclopramide. Prolactin and aldosterone levels were measured to assess metoclopramide's endocrine effects. Six salt-loaded subjects were studied by standard renal clearance techniques during water diuresis. Dopamine infusion produced an increase in renal plasma flow, fractional excretion of sodium, osmolar and free water clearances, urine volume, and solute delivery out of the proximal tubule. Solute and fluid absorption decreased in the distal nephron. These effects were evident within the first hour and peaked during the third hour. Metoclopramide slightly attenuated the dopamine-induced increase in renal plasma flow; statistical significance was obtained only during the second hour. None of the other renal function changes were inhibited. Serum prolactin and aldosterone levels were significantly increased following metoclopramide. Dopamine infusion attenuated the rise in prolactin levels but did not significantly affect aldosterone levels. The variance between previous reports and the present one may be due to the use of water diuresis, salt-loading, or methodological factors. Metoclopramide infused at 0.1 mg/kg/h appears selective for DA2 receptors, and low-dose dopamine-induced changes in renal function are DA1 receptor-mediated.

Effect on the endocrine system of a new dopaminergic agent, ibopamine.

Ibopamine, an oral dopaminergic and adrenergic agent, was given to 19 healthy men to investigate the effect of this dopamine analogue on carbohydrate metabolism. In a three-part study six subjects received ibopamine alone, seven subjects were pretreated with metoclopramide (a dopamine antagonist), and six subjects received phentolamine (an alpha-receptor antagonist) and propranolol (a beta-receptor antagonist) to study the specific mechanisms involved. In these single-blind, controlled, randomized studies, effects on fasting glucose, insulin, glucagon, and prolactin were evaluated. Ibopamine, 300 mg, produced a statistically significant increase in fasting glucose and insulin levels but had no effect on glucagon or prolactin levels. Pretreatment with metoclopramide or phentolamine did not block these effects, but pretreatment with propranolol significantly (P less than 0.05) blunted the increase in fasting glucose and insulin levels. These findings indicate that, unlike other dopaminergic agonists, administration of ibopamine results in increased glucose levels without affecting glucagon. The effect on glucose is mediated through stimulation of beta-adrenergic receptors.

The effect of acetaminophen on the disposition of fenoldopam: competition for sulfation.

Both fenoldopam and acetaminophen undergo conjugation with sulfate in humans. The present study was undertaken to determine if a metabolic interaction exists between these two compounds in humans. Twelve healthy male volunteers participated in a single-dose crossover study with 100 mg fenoldopam (capsule) alone or in combination with 1000 mg acetaminophen. The effects of chronic acetaminophen dosing (1000 mg three times/day for 7 days) on a single 100 mg tablet of fenoldopam were studied in a second crossover study in seven additional volunteers. Concomitant dosing with fenoldopam with acetaminophen resulted in increases in peak fenoldopam plasma concentration and AUC after both single (+32% and +50%, respectively) and chronic (+73% and +66%, respectively) acetaminophen dosing. Decreases in peak plasma concentrations and AUC for fenoldopam's sulfated metabolites were seen in both studies. These findings indicate a metabolic basis for the interaction between fenoldopam and acetaminophen, presumably through a competition for inorganic sulfate.

The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics.

Fenoldopam, a dopaminergic agonist, was administered intravenously to 18 healthy male subjects in doses ranging from 0.025 to 1.0 microgram/kg/min for 2 hours. Three subjects were studied in a three-way crossover of fenoldopam at doses of 0.025, 0.10, and 0.50 microgram/kg/min. Fenoldopam decreased diastolic blood pressure and increased pulse rate without changing systolic blood pressure. Fenoldopam produced dose-related increases in para-aminohippuric acid clearance up to 75% at the 0.50 microgram/kg/min dose. This increase in renal blood flow was accompanied by increases in urine volume, water, and solute excretion; glomerular filtration rate was unchanged. Doses greater than 0.25 microgram/kg/min caused flushing and nasal congestion. The dopamine receptor antagonist metoclopramide (0.1 mg/kg/hr) did not block the systemic hemodynamic effects of fenoldopam but attenuated the increase in para-aminohippuric acid clearance. Fenoldopam plasma levels achieved steady state between 30 and 120 minutes after the start of the infusion and were linear with respect to infusion rate. Our findings show that intravenous fenoldopam causes systemic arteriolar vasodilation, accompanied by renal vasodilation and increased sodium excretion.

Temelastine, a new H1-receptor antagonist.

Temelastine is a selective, competitive histamine H1-receptor antagonist which does not penetrate the central nervous system. The effect of varying doses of temelastine was compared in a randomized, double-blind, controlled study by measuring the inhibition of cutaneous histamine wheals. In twelve subjects single oral doses of 50, 100 and 200 mg of temelastine produced dose-dependent reductions in wheal areas. The inhibition of wheal size was maximal by 2 hr after dosing and was present at 8 hr. At 2 hr the 50, 100, and 200 mg doses reduced the wheal size by 53, 64, and 78%, respectively. Chlorpheniramine, 4 mg, reduced wheal size by 32% at the same period. The ability of temelastine to antagonize the histamine-induced skin reaction over 20 hr was evaluated in a second randomized, double-blind study. Eight subjects participated. Temelastine, 100 mg, produced reductions of 64, 49, 56 and 51% in histamine wheal area at 8, 12, 16 and 20 hr, respectively. Plasma concentrations at these times were 4.04, 2.77, 1.88, and 1.44 mumol/l, respectively. These data suggest that blood levels as low as 1.44 mumol/l may be sufficient to produce an antihistaminic effect, and that daily or twice daily dosing with 100 mg may be adequate to control allergic symptoms.

Selective peripheral dopamine-1 receptor stimulation with fenoldopam in human essential hypertension.

SKF 82526-J, or fenoldopam, a benzazepine derivative, is a selective dopamine-1 (DA-1) agonist devoid of activity at dopamine-2, alpha- or beta-adrenergic receptors. We studied SKF 82526-J in 10 patients with essential hypertension and five normal control subjects on constant 150-meq sodium, 60 meq potassium intake. In the hypertensive patients, during a 6-d placebo period supine blood pressure and heart rate were stable at 156 +/- 6/105 +/- 4 mmHg and 76 +/- 5 beats/min, respectively. In response to a single oral dose of 100 mg of SKF 82526-J, supine blood pressure decreased to a nadir of 141 +/- 5/89 +/- 8 mmHg (P less than 0.0001) at 90 min and remained decreased at 145 +/- 6/99 +/- 3 mmHg (P less than 0.0001) at 4 h. Heart rate increased to 91 +/- 5 beats/min (P less than 0.002), but returned to control levels (82 +/- 5 beats/min) at 4 h. Renal blood flow increased from 371 +/- 57 to a peak of 659 +/- 104 ml/min and renal vascular resistance fell from 34 +/- 5 to 19 +/- 2 dyn sec cm-5 X 10(3) (P less than 0.01). Urine volume, sodium and fractional sodium excretion, and plasma renin activity were increased as a result of SKF 82526-J administration. During the ensuing 3 wk of SKF 82526-J, blood pressure remained decreased and returned to control levels after placebo administration. In contrast, in normal subjects SKF 82526-J administration was associated with a small transient reduction in diastolic pressure only. These results suggest that reduced dopaminergic activity expressed at the peripheral DA-1 receptor may contribute to the pathophysiology and/or maintenance of increased blood pressure in essential hypertension. In addition, the results suggest that peripheral DA-1 receptor stimulation with SKF 82526-J may be efficacious in the treatment of human essential hypertension.

Five cephalosporins: pharmacokinetics and their relation to antibacterial potency.

In a group of adult volunteers, pharmacokinetic profiles of five cephalosporins were correlated with their minimal inhibitory concentrations (MICs90) against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter aerogenes. Subjects received the following intravenous regimens in a randomized, crossover fashion: (1) 0.5 gm, 1 gm, or 2 gm of cefazolin; (2) 2 gm of cephalothin; (3) 1 gm of cephapirin; (4) 1 gm of cefoxitin; or (5) 0.5 gm of cefamandole. The 500-mg dose of cefazolin produced serum concentrations that exceeded those of any of the other cephalosporins at 0.5, 1, 2, 4, and 6 hours after administration. The area under the curve for this dose of cefazolin was at least twice that of any of the other antibiotics. Two hours after a 500-mg dose of cefazolin, serum levels exceeded the MIC90 for all seven groups of pathogens; at six hours, the 500-mg dose of cefazolin continued to achieve serum levels above the MIC90 against the majority of bacterial groups. In contrast, at two hours after administration none of the other cephalosporins maintained serum levels above the MIC90 for all pathogens; at six hours, the levels of cephapirin were adequate to inhibit the two streptococci, but serum levels of all other cephalosporins were inadequate to inhibit any of the pathogens. These data indicate that a 500-mg dose of cefazolin maintains serum levels above the MICs90 longer than any of the other cephalosporins tested and support the use of a 500-mg dose of cefazolin every eight hours for surgical prophylaxis and treatment of most community-acquired infections. Such a comparatively low dosage offers substantial savings to both patient and hospital.

A new oral renal vasodilator, fenoldopam.

Fenoldopam, a dopamine agonist, was evaluated in renal clearance studies during water diuresis after oral doses of 25, 50, and 100 mg. After the 100-mg dose there was an increase in urine flow rate, paraaminohippurate clearance, free water clearance, and an increase in the fractional excretion of sodium, calcium, and uric acid. These effects were evident within the first hour, peaked during the second hour, and lasted about 3 hr. Doses of 50 and 25 mg induced smaller increases. There was no significant change in inulin clearance at any dose. To elucidate the mechanism of action, the studies were repeated after treatment with a dopamine-receptor antagonist (metoclopramide). Metoclopramide greatly diminished the renal effects of fenoldopam. These findings indicate that fenoldopam is an active renal vasodilator in man and increases urine volume, free water clearance, and fractional excretion of sodium by stimulation of renal dopamine receptors.

Ceftizoxime kinetics and renal handling.

The kinetics and renal handling of ceftizoxime were examined after intravenous and intramuscular injection and the effect of probenecid on its excretion was investigated. Peak serum level after 1000 mg IV was 60.5 microgram/ml and half-life (t 1/2) was 1.4 hr. Peak serum level (40.9 microgram/ml) was reached 1 hr after 1000 mg IM. When probenecid was added to the 1000-mg IM dose the peak level was 44.3 microgram/ml at 1 hr and serum levels at 2, 4, 6, and 8 hr were all higher than after ceftizoxime alone (P less than 0.01). The 1.85-hr t 1/2 of ceftizoxime alone was extended to 2.29 hr when probenecid was added. Ceftizoxime was shown to be actively secreted by the renal tubule; this secretion was decreased by probenecid.

Kinetics and renal handling of cefonicid.

Cefonicid kinetics were determined after intravenous and intramuscular injection and the renal handling of the drug was examined, including the effect of probenecid on its excretion. Peak serum levels after 1000 and 500 mg intravenously was 221 and 91 micrograms/ml. The half-life (t1/2) was the same for both regimens (3.5 hr). Intramuscular injection of the 1000- and 500-mg doses resulted in peak serum levels of 112 and 40 micrograms/ml. When probenecid was given with the 500-mg dose, the peak serum level was 61 micrograms/ml and the time to peak level rose from 1.3 to 2.5 hr. The t1/2 after 1000 and 500 mg alone was much the same at 4.8 and 4.9 hr. The addition of probenecid to the 500-mg dose extended the t1/2 and 7.5 hr. Renal clearance, excretion, and secretion rates for cefonicid were reduced by the addition of probenecid. Cefonicid's long t1/2 and high blood levels may provide clinical efficacy with a single daily dose.

Ticrynafen in anephric patients: effects on uric acid and pharmacokinetics.

Ticrynafen was given to 6 anephric patients undergoing maintenance hemodialysis. Ticrynafen was given daily for the 3 days between hemodialyses. Ticrynafen had no effect on the interdialysis rise in serum uric acid levels. Ticrynafen did not accumulate in serum, but levels of metabolites continued to rise over the 3 days. Hemodialysis (5 hr) reduced levels of ticrynafen by 38% but had less effect on metabolite levels. There was no effect on serum cholesterol or triglycerides.

Oxypurinol nephrolithiasis in regional enteritis secondary to allopurinol therapy.

A patient with regional enteritis and recurrent uric acid nephrolithiasis was treated with allopurinol. While on 600 mg of allopurinol daily, she began to pass many small, soft, yellow stones. Analysis of the stones by liquid chromatographic and gas chromatograph/mass spectrometric techniques revealed that their major constituent was oxypurinol, a metabolite of allopurinol. Metabolic studies of the patient indicated that increasing doses of allopurinol were associated with increases in xanthine and oxypurinol excretion, while uric acid excretion was not reduced. This case illustrates a complication of high-dose allopurinol therapy in the treatment of uric acid nephrolithiasis.

Studies with a PNMT inhibitor.

DCTQ (SK&F 64139) is a potent inhibitor of both adrenal and central nervous system (CNS) phenylethanolamine N-methyltransferase (PNMT). In animal studies, a plasma level of 0.35 microgram/ml was associated with 50% inhibition of both adrenal and central PNMT. We performed single-dose phase I studies with DCTQ in man. Plasma drug levels up to 6.26 microgram/ml were readily obtained. There were few subjective and no objective clinical changes. DCTQ did not alter blood pressure or cause CNS symptoms in man. Furthermore, resting plasma and urinary catecholamines did not change after DCTQ. The study suggests that acute inhibition of PNMT under resting conditions is without significant clinical effect.

Ticrynafen: site of natriuretic activity.

Studies were performed with ticrynafen (tienilic acid) to determine its natriuretic site of action, detailed electrolyte excretion, and its effect on acid excretion and bicarbonate reabsorption. With 500 and 1,000 mg oral doses under conditions of water diuresis, there was a decrease in free water excretion as osmolar clearance increased. During hydropenia, there was no change in free-water reabsorption as osmolar clearance increased. Maximum sodium excretion reached 5.2% of the filtered load. At 500 mg doses, there was no effect on phosphate excretion; with 1,000 mg doses, there was a reduction in phosphate excretion. During bicarbonate infusion, there was no change in the absolute or percent reabsorption of bicarbonate. After chronic administration of ticrynafen, there was no impairment of excretion of al acute acid load. Uric acid excretion increased at least threefold in all studies. The studies indicate that at 500 and 1,000 mg oral doses, ticrynafen has the characteristics of a diuretic which is active in the cortical diluting segment of the distal nephron.