Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis.

PURPOSE: To administer recombinant erythropoietin to patients with rheumatoid arthritis who had significant anemia, while monitoring hematologic and rheumatologic clinical responses as well as potential toxicity. PATIENTS AND METHODS: Seventeen patients with rheumatoid arthritis from five rheumatology care settings were studied. The patients had initial hematocrits of 34% or less and stable clinical status, and were not being treated with second-line drugs or corticosteroids. An 8-week randomized double-blind study involving various dosages of recombinant erythropoietin, as well as placebo, was followed by a 24-week open-label study in which dosage could be titrated to achieve a normal hematocrit. RESULTS: In the 8-week randomized study, four of 13 patients who received injections of recombinant erythropoietin showed a hematologic response, arbitrarily defined as at least a 6-unit increase in hematocrit. None of four placebo-treated patients showed a meaningful hematologic response. All 11 patients who completed the subsequent 24-week open-label study reached a normal hematocrit level at some time during the study, and 10 of 11 showed an increase of hematocrit 6 units or greater. At least one adjustment, i.e., an increase, decrease, or omission of the erythropoietin dosage, was required in all patients to maintain the hematocrit at a target range of 35% for women or 40% for men. Meaningful changes were not seen in patients' capacity to perform activities of daily living or pain levels during either the 8-week randomized study or the 24-week open-label study. No adverse effects were associated with recombinant erythropoietin therapy. CONCLUSION: Patients with rheumatoid arthritis showed excellent hematologic responses to recombinant erythropoietin, without toxicity, during careful monitoring for appropriate dosage adjustment, although a meaningful change in rheumatologic clinical status was not seen.

Central cardiovascular effects of SQ 14,225, an angiotensin-converting enzyme inhibitor in chloralose-anesthetized cats.

Experiments were conducted in chloralose-anesthetized cats to investigate the central and peripheral cardiovascular effects of a new orally active angiotensin-converting inhibitor, SQ 14,225 (3-mercapto-2-D-methylpropanoyl-L-proline). I.v. administration of SQ 14,225 (0.31-3100 microgram/kg) antagonized the pressor responses to angiotensin I (AI) (310 ng/kg) i.v. in a dose-related manner but did not alter responses to angiotensin II (AII) (200 ng/kg) i.v. Similarly, intracerebroventricularly (i.c.v.) administered SQ 14,225 (0.31-310 microgram/kg perfused over 10 min) produced dose-related decreases in the centrally mediated pressor responses and heart increases elicited by AI (310 ng/kg) i.c.v. The central responses to AII (200 ng/kg) i.c.v. were not affected by SQ 14,225. Passage of SQ 14,225 out of the ventricular system into the systemic circulation was detected, but only at doses greater than that required to antagonize central AI responses. Doses of SQ 14,225 (310 microgram/kg and 3.1 mg/kg) i.v. which maximally inhibited i.v. AI responses, had no effect upon central AI activity. This finding suggests that passage of SQ 14,225 across the blood brain barrier into the central nervous system is restricted. Peripheral or central administration of SQ 14,225 produced only minimal transient decreases in blood pressure (less than 10 mm Hg). The results of these studies indicate that SQ 14,225 is a potent inhibitor of AI conversion in the brain as well as in the peripheral circulation.

Centrally mediated pressor response to metiamide as a result of GABA-receptor antagonism.

The mechanism of the pressor response to metiamide was examined in anesthetized cats. Intravenous administration of metiamide had no effect on blood pressure. Infusion into the lateral ventricle (10 mg/kg/min for 10 min), caused a marked pressor response which was due to an increase in sympathetic outflow since pretreatment of cats with guanethidine completely prevented it. In a rat brain synaptosome preparation, both metiamide and cimetidine displaced [3H] CABA. These data strongly suggest that metiamide increases blood pressure in the cat through a central mechanism involving GABA-receptor antagonism.

Hypotension induced by inhibition of angiotensin-converting enzyme in pentobarbital-anesthetized dogs.

The mechanism of the hypotensive response produced by inhibition of the angiotensin converting enzyme was studied in pentobarbital anesthetized dogs. A recently developed potent inhibitor of the converting enzyme, SQ 14,225 (D-3-mercapto-2-methyl propanoyl-L-proline), administered i.v. to intact dogs resulted in a rapid marked decrease in blood pressure. In nephrectomized dogs, SQ 14,225 retained significant hypotensive activity, although the absolute magnitude of the decreases in blood pressure were less than had been observed in dogs with intact kidneys. SQ 14,225 also lowered blood pressure when administered to intact dogs in which angiotensin II receptors had been blocked with the receptor antagonist Sar1,Ala8-angiotensin II. This apparent ability of SQ 14,225 to decrease blood pressure in the absence of a functional renin angiotensin system was shared by a structurally dissimilar, nonapeptide, angiotensin converting enzyme inhibitor, SQ 20,881 (Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro). SQ 20,881 also produced significant decreases in blood pressure in nephrectomized dogs. These findings indicate that the angiotensin converting enzyme inhibitors, SQ 14,225 and SQ 20,881 may lower blood pressure in anesthetized normotensive dogs via a mechanism unrelated to either the renin angiotensin system or the renal kinin system.

The effect of food or milk on the bioavailability of etintidine in healthy subjects.

A three-way crossover study was conducted in 24 normal, male volunteers to compare the bioavailability of etintidine from capsules (2 X 200 mg) taken under fasting conditions, with food and with milk. Blood samples were collected prior to and at various times after each treatment and plasma levels of etintidine were determined by high performance liquid chromatography. Statistical analysis of the plasma etintidine concentration data indicated that while neither food nor milk had an apparent effect (p greater than 0.05) on the rate of etintidine absorption, both food alone and milk alone slightly decreased the extent of etintidine absorption. Mean bioavailability parameters of etintidine obtained following the administration of etintidine with food, milk or under fasting conditions are 5.28, 5.26 and 5.88 micrograms.h/ml, respectively (for AUC) and 1.75, 2.18 and 2.59 micrograms/ml, respectively (for Cmax), and 1.23, 1.01 and 0.91 h, respectively (for tmax). Symmetrical 95% confidence interval analyses showed that the observed decreases of less than 11% in the AUC values of etintidine following the concomitant administration of food or milk were within 17% of the fasting value and, therefore, may not be of clinical significance.

Single-dose and multiple-dose pharmacokinetics of etintidine in healthy volunteers.

The present study was designed to determine the single- and multiple-dose pharmacokinetic profiles of the H2 receptor antagonist etintidine in healthy volunteers. Etintidine was rapidly absorbed and eliminated after the oral administration of 300 mg base equivalent of etintidine HCl in a capsule formulation to 11 healthy subjects. Comparison of the pharmacokinetics after a single dose and during steady state showed no significant differences (p greater than 0.05) in the mean values of Cmax, tmax, oral clearance, elimination rate constant, and renal clearance, indicating no significant accumulation of etintidine and no apparent time-dependent changes in the pharmacokinetics of etintidine during multiple dose administration.

Clinical pharmacokinetics of etintidine.

The pharmacokinetics of etintidine (E), a potent H2 blocker, were studied in 12 normal, fasted subjects. The subjects received five ascending doses of E HCl in capsules at 72-h intervals. Blood and urine samples were collected and the plasma and urine levels of E were determined by HPLC. Following oral administration, plasma E levels showed double peaks in half of the subjects. Mean Cmax (0.42, 2.11, 3.82, 4.50, and 7.15 micrograms ml-1), AUC0-infinity (0.96, 4.94, 11.3, 17.5, and 24.5 h micrograms ml-1), and the amount of E excreted unchanged in 72 h (20, 54.8, 170, 320, and 371 mg) were determined. These parameters indicate the amount of E absorbed increased linearly with dose for each individual. Renal clearance was independent of the dose and the mean value (16.6 lh-1) was about twice that of the creatinine clearance (which did not significantly change as a result of E treatment), indicating that E is actively secreted into the renal tubules. As E was eliminated rapidly from the body (t1/2 less than 2 h), no substantial accumulation of E is expected after multiple dose treatment.

Antihypertensive activity of captopril (SQ 14,225), an orally active inhibitor of angiotensin converting enzyme in conscious two-kidney perinephritic hypertensive dogs.

Conscious dogs made hypertensive by wrapping both kidneys with cellophane were treated daily with a single dose of captopril (31 mg/kg p.o.), an inhibitor of the angiotensin converting enzyme, or with placebo (lactose, 31 mg/kg p.o.) for a period of 13 weeks. Blood pressures were recorded indirectly from a forepaw by using a Roche ultrasonic pressure transducer (Arteriosonde). Treatment with captopril resulted in decreases in blood pressure (25-30 mm Hg) that were maximal at 3 to 6 hr with no associated changes in heart rate. The captopril-induced hypotensive effect was maintained throughout the 13-week treatment period, and after the termination of captopril dosing, pressure rose slowly over the next 72 hr to a level not significantly different from placebo-treated dogs. Plasma renin activity (PRA) in the hypertensive dogs at the time treatment was initiated was not different from the same animals when they were normotensive. In captopril-treated animals, PRA increased 3- to 4-fold after each dose of the drug was given, reaching a maximum at 3 to 6 hr, a time corresponding to the maximal blood pressure decrease. PRA gradually declined but did not reach control levels before the next dose of captopril was administered. In animals treated with placebo, PRA remained at levels not significantly different from normotensive dogs during the entire treatment period. After termination of captopril administration, PRA slowly returned to pretreatment levels; the return of PRA paralleled the recovery of blood pressure. The results indicate that captopril is effective in reducing blood pressure for an extended period of time in a hypertensive model in which the level of activity of the renin angiotensin system is not elevated.