Fenoldopam reverses cyclosporine-induced renal vasoconstriction in kidney transplant recipients.

Cyclosporine causes renal vasoconstriction and reduced renal blood flow that may contribute to chronic nephrotoxicity. This effect has not been consistently reversed by available pharmacologic agents. The efficacy of orally administered fenoldopam, a dopamine-1 (DA-1) agonist with renal vasodilator properties, was evaluated in six patients whose condition was stable 3 to 6 months following renal transplantation. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate (PAH) clearances, respectively, at baseline, after the acute oral administration of 100 mg of fenoldopam, and following 3 weeks of chronic oral fenoldopam therapy (100 mg thrice daily). Mean ERPF increased from 3.15 +/- 0.17 mL/s/1.73 m2 (189 +/- 10 mL/min/1.73 m2) at baseline to 3.48 +/- 0.17 mL/s/1.73 m2 (209 +/- 10 mL/min/1.73 m2) 4 hours after acute administration of fenoldopam (P = 0.04). Urine flow rate and fractional excretion of sodium also increased after acute administration, but not significantly. Mean systolic (SBP) and diastolic blood pressure (DBP) decreased maximally by 18 and 6 mm Hg, respectively, and mean pulse rate increased maximally by 8 bpm between 75 and 90 minutes after both acute and chronic administration. GFR was unchanged following both acute and chronic administration. The increase in ERPF was not maintained to the end of the dosing interval during chronic administration, probably due to the short half-life of fenoldopam. However, the renal vasodilatory response was still observed 3 to 4 hours after readministration of the drug following 3 weeks of oral dosing. Thus, fenoldopam significantly reverses the renal vasoconstriction caused by cyclosporine in renal transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

A retrospective analysis of fenoldopam renal excretion in 65 subjects: evidence for possible intrarenal formation of fenoldopam from its metabolites.

Clinical studies have suggested that the dopamine DA1 agonist, fenoldopam, may exhibit nonlinear renal excretion in humans. A retrospective population pharmacokinetic analysis of the renal excretion of fenoldopam and one of its major metabolites, fenoldopam-8-sulfate, was conducted in 65 healthy volunteers to examine this phenomenon. Fenoldopam-8-sulfate exhibited a mean (+/- SE) renal plasma clearance of 129 +/- 4 ml/min, which was independent of its AUC. In contrast, fenoldopam renal plasma clearance ranged from 2220 to 150 ml/min and decreased nonlinearily with increasing fenoldopam AUC. Fenoldopam renal clearance was characterized as a function of fenoldopam AUC using a nonlinear saturation model. The analysis predicted an initial maximal renal clearance of 2852 ml/min, which decreased to 78 ml/min at maximal inhibition. The fenoldopam AUC required to half-saturate fenoldopam renal clearance was 5.2 ng x hr/ml. The elevated clearance values for fenoldopam, beyond normal physiologic limits for renal blood flow in man, suggest that intrarenal formation of fenoldopam from one or more of its circulating metabolites may be contributing to the observed nonlinear decreases in fenoldopam renal excretion. Preliminary data from our laboratory suggest that in vivo desulfation of fenoldopam-8-sulfate to fenoldopam does occur in the dog.

Effect of a new synthetic hexapeptide to selectively stimulate growth hormone release in healthy human subjects.

Growth hormone-releasing peptide (GHRP, SK&F 110679) is a hexapeptide (His-DTrp-Ala-Trp-DPhe-LysNH2) that selectively stimulates the release of growth hormone (GH) but not other pituitary hormones in vitro and in vivo in a variety of animal species. GHRP was administered to 17 normal men at doses of from 0.05 to 2.5 micrograms/kg as a 30 min intravenous infusion. Eight of the men were infused with saline as a control. Serum GH increased consistently at doses of 0.25 microgram/kg and above during the infusion of the peptide, peaked at 45 min and then decreased to baseline values by 210 min. The mean peak serum GH concentrations (+/- SE) in response to GHRP infusion were 17.8 +/- 6.1 micrograms/L at a dose of 0.25 microgram/kg (n = 4, p = .03 vs saline), 38.3 +/- 9.2 micrograms/L at 0.5 microgram/kg (n = 4, p = .04 vs saline) and 63.0 +/- 5.4 micrograms/L at 1.0 microgram/kg (n = 4, p = .002 vs saline). Serum LH, FSH, TSH and ACTH were unaffected by GHRP administration. GHRP was safe and well-tolerated in all men. GHRP infusion resulted in a dramatic, selective and dose-dependent increase in serum GH concentrations.

Academic-industrial cooperative graduate program in clinical pharmacology.

Because a new level of sophistication among clinical investigators is necessary for the testing of new agents in human subjects, a close integration of basic science, clinical medicine, and pharmaceutical medicine is required. Experts from the Departments of Pharmacology and Medicine at Temple University School of Medicine and Smith Kline and French Laboratories have combined to form a joint training program in clinical pharmacology. This structured graduate program for physicians couples didactic courses with a defined program of independent research, leading to a Master of Science degree in pharmacology. The development of new technologies and the transfer of them from the "bench to the bedside" demands that the clinician have special competence in clinical pharmacology. This unique joint academic-industrial program sets the goals ensuring that this objective is met.

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 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.

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.

Pharmacokinetics and mode of action of tienilic acid.

A review of the absorption, distribution, metabolism and excretion of ticrynafen (tienilic acid) in 8 animal species, including man, is presented. Although some species effects are apparent, ticrynafen absorption is essentially complete following oral administration. The compound is extensively bound to plasma proteins, primarily albumin. Consequently, tissue concentrations are generally lower than plasma concentrations. Plasma and whole body clearance of ticrynafen is rapid due both to metabolism and to extensive renal excretion of the compound and its metabolites. Male/female differences in renal excretion occur, with a subsequent effect on ticrynafen metabolism. Ticrynafen is an inhibitor of reabsorption of sodium and uric acid by the kidney. This inhibitory effect, within the renal tubular lumen, accounts for its diuretic and uricosuric activity and could account for its antihypertensive activity, although a direct effect has also been claimed. Ticrynafen is also a classical example of a competitive inhibitor of organic acid transport in the kidney and other organs. Much of the drug-drug interaction involving ticrynafen is understandable due to its effect on transport. However, potentiation of anticoagulant activity appears to involve some direct effects upon warfarin metabolism although ticrynafen, in general, is not an enzyme inducer or inhibitor. Toxicity of ticrynafen is low in all animal species.

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.