renal effects of intermittent versus continuous infusion of ibuprofen in the primate

PROSTAGLANDINSLEUKOTRIENES ANDESSENTIALFATTYACIDS

Prostaglmdms Leakmimes and Esscnt~al Fatty Acids (1994) 5 I, 249-256

0 Longman Group Ltd 1994

Renal Effects of Intermittent Versus Continuous Infusion of Ibuprofen in the Primate

P. S. Rae*‘, D. Cavanagh* and J. R. Dietz+

*Departments of Obstetrics and Gynecology, and tPhysiology and Biophysics, The University of South Florida, College oj.Medicine, 12901 Bruce B. Downs Blvd. Tampa, Florida 33612. USA (Reprint requests to PSR)

ABSTRACT. The clinical use of nonsteroidal anti-inflammatory drugs is gaining wide acceptance and acute oliguric renal failure in association with the administration of ibuprofen has been reported. This study was designed to evaluate the renal effects of intermittent versus continuous intravenous infusion of ibuprofen (Motrin) over a 24-h period in the anesthetized non-pregnant baboon. A total of 50 mg/kg of ibuprofen was either infused continuously or given as a bolus in four divided doses (intermittent). Control animals received only normal saline. Mean aortic pressure showed a tendency to decrease with time in all groups studied with a significant decrease occurring in the infusion group. There were no significant changes in the renal artery flow, renal resistance, central venous pressure and heart rate within the groups. Serum urea nitrogen decreased and was significantly different from the baseline value at 24 h in the infusion group. Serum creatinine, however, showed no such changes. Although, urinary output and creatinine clearance showed a tendency to decrease in the treated groups, it was not significantly different. Plasma renin activity decreased from 9.95 to 2.3 ng/ml/hr in the control group but showed no significant changes in others. Serum levels of angiotensin converting enzyme were well maintained. The circulating levels of ibuprofen reached a steady state after 2 h in the infusion group. The results of this study demonstrate that continuous infusion of ibuprofen does not possess an advantage over its intermittent administration. Despite the modifications we have observed in renal flow and function, this drug appears to be safe in the dose levels we have used in these experiments. -

The nonsteroidal anti-inflammatory drugs (NSAIDs)

constitute a wide-ranging category of agents falling within a number of chemical classifications. The clinical

use (1-4) of NSAIDs is gaining wide acceptance and

it has been estimated these agents were recommended for therapy at a rate of 49 546 million times by physi-

cians in 1987 (5). There is general agreement that NSAIDs act by inhibiting cycle-oxygenase, thereby re-

ducing the biosynthesis of prostaglandins (1,6-g). Renal prostaglandins function as vasodilators in the renal

circulation and when their production is inhibited, particularly in association with renal ischemia, the pro- tective effect is no longer available and results in increased

renal ischemia. There is experimental evidence to sup-

port this point of view (9-l 1). Most of the available NSAIDs have been implicated

in the development of acute renal failure (4) as a result

of renal hypoperfusion (12). acute tubular necrosis (13) and interstitial nephritis (14). In association with this, oliguria, sodium and water retention, hyperkalemia and proteinuria have been observed (4). Of the newer

L>are received 19 April 1994

Dare accepted 3 May 1994

NSAIDs, the propionic acid derivatives are well ac-

cepted because of their excellent tolerance. Ibuprofen belongs to this category of drugs with a normal serum

half-life of approximately 2.5 h (15) and is primarily

eliminated by the kidneys after metabolic transforma-

tion. There is a paucity of information pertaining to the

intravenous administration of ibuprofen and renal effects. Whether effects of continuous infusion of ibuprofen differs from that of intermittent administration is not

clearly understood. Because nonhuman primates demonstrate marked similarities to humans in almost all aspects

of their anatomy, endocrinology and physiology (16) baboons were used in these experiments. This study was

designed to evaluate several cardiovascular parameters and blood gases, with particular emphasis on renal

function, and renin-angiotensin system in response to continuous intravenous infusion versus intermittent

injection of ibuprofen over a 24-h period.

MATERIALS AND METHODS

Adult, non-pregnant, female baboons (Papio anubis) with an average body weight of 11.75 + 0.47 (SD) kg

249

250 Prostaglandins Leukotrienes and Essential Fatty Acids

were used in this study. The animals were fed and

cared for according to the guidelines established by the

American Association of Laboratory Animal Care. This study was approved by the Institutional Animal Care and

Use Committee of the University of South Florida. They

were fasted overnight prior to the experiment, but water was given ad libitum. The following day they were se-

dated with ketamine hydrochloride given intramuscularly

(5 mg/kg), and anesthetized with pentobarbital sodium (25-30 mg/kg) given intravenously. A peripheral vein

was cannulated and each animal received 5% dextrose

in isotonic saline (20 ml/h) as an intravenous drip

and anesthetic as required during the course of the

experiment. The volume of blood withdrawn, and the

urine output, was replaced isovolumetrically with isot-

onic saline. In the instances where plasma was obtained, the cells were resuspended in isotonic saline and were

returned to the animal. After the surgical procedures were completed, 60 min was allowed for stabilization

before obtaining baseline values. All infusions were car- ried out using a Harvard infusion pump. Rectal tempera-

ture was measured using a Cole Parmer thermistor probe

and a thermometer (8502-20). This was maintained at or

near the baseline value by the use of a heat lamp. Three groups were studied with 2 animals in the

vehicle control group receiving only isotonic saline

during the course of the experiment. The bolus group consisted of 4 animals and ibuprofen (Motrin) was

injected intravenously over 3 min in a dosage of 12.5 mg/kg of body weight at 6-h intervals over a 24-h period. The infusion group also consisted of 4 animals.

Following a priming dose of 12.5 mg/kg of ibuprofen,

the remainder was given as a constant intravenous infusion over a 24-h period and the total amount admin-

istered was exactly 50 mg/kg of body weight. Ibuprofen

was supplied by The Upjohn Company, Kalamazoo,

Michigan in sealed vials of 10 ml each and with each milliliter containing 50 mg equivalent of ibuprofen. To

avoid hemolysis, ibuprofen was diluted with approximately three times its volume of normal saline and

was either injected or infused intravenously. Following completion of the experiments, surgical incisions were

closed by standard techniques and all animals were returned to their cages. The baboons were observed

carefully for the next 14 days and those that have survived were considered to be permanent survivors.

Hemodynamic studies

Aortic pressure was measured by inserting a polyethylene catheter into the femoral artery through a ‘cut-down’ in the right groin and was advanced into the abdominal aorta. The right femoral vein was exposed and two polyethylene catheters were introduced, with one resting proximal to the right atrium for the measurement of central venous pressure and another in the abdominal vena cava for infusion purposes. Pressure transducers (Hewlett-Packard, 1290A) and a Sanbom recorder (7700

series) were used for the monitoring of the aortic and

central venous pressures. The heart rate was calculated

from the arterial pulse tracings. The left renal artery

was exposed extraperitoneally and the flow was meas-

ured using an electromagnetic flow-meter (Carolina Medical Electronics - Model 501) and non-cannulating

electromagnetic flow probes (8-10 mm in circumference).

Renal artery pressure was measured as renal orifice pressure, and renal vascular resistance was calculated

from directly measured blood flow. A foley catheter

(10 fr, C. R. Bard, Inc.) was introduced into the bladder for the continuous measurement of urinary output.

Blood chemistry, blood gases and hematologic studies

The intraarterial catheters were cleared with 5 ml

of blood. The specimens were withdrawn into plastic disposable syringes for the transfer to sterile glass tubes,

and the first 5 ml of blood was returned to the animal. Samples were drawn immediately before the infusion

was begun, and at 6-h intervals thereafter. Following

clot formation, serum was separated by centrifugation. A serometer model 370 (Mallinckrodt), and the corre-

sponding quantitative colorometric test kits were used

for the estimation of serum glucose, and blood urea nitrogen (BUN). For the determination of hematocrit,

platelets, and white cell counts the blood was collected in tubes containing ethylenediamine tetraacetic acid

(EDTA) and was estimated as previously described (17). Blood gas determinations were done from samples drawn from the intraarterial catheters into heparinized

syringes and were immediately analyzed for pH, PO2 and PC02 (17).

Electrolytes and creatinine clearance studies

Blood samples were drawn into heparinized tubes and plasma was obtained following centrifugation. A flame photometer (Instrumentation Laboratory, Inc. Lexington,

Massachusetts, USA) was used to analyze for sodium and potassium concentration prior to the infusion, and at

6-h intervals thereafter in both plasma and urine. The rate of sodium reabsorption (%) was calculated for each

sample from the control and treated animals. After the baseline values were obtained, serum and

urine creatinine was measured at 6-h intervals. From this data, the endogenous creatinine clearance was calculated

according to standard methods. Serum osmolality was measured with the use of a micro osmometer (Model 5004, Precision Systems, Inc., Natick, Massachusetts, USA).

Plasma renin activity (PRA)

Blood samples were drawn prior to infusion being commenced and at 6-h intervals thereafter from the intraarterial catheter into tubes containing EDTA

Renal Effects of Intermittent Versus Continuous Infusion of Ibuprofen in the Primate 25 I

( 1 mg/ml). and were immediately placed on ice. Follow-

ing centrifugation in a refrigerated centrifuge at 4”C, the plasma was obtained and kept frozen at -20°C until further analysis. Plasma renin activity was measured as

described previously (18). In brief, plasma samples

were dialyzed for 24-h in a cold room at 5°C with

a phosphate buffer (pH 5.3). 50 microliter aliquots

were incubated for 1 h at 37°C in the presence of

diisoprophylfluorophosphate to prevent breakdown of formed angiotensin 1. Angiotensin I was measured by

radioimmunoassay ( 19) using “51 angiotensin I from

New England Nuclear, Boston, Massachusetts, and angiotensin I standard from Sigma Chemical Company, St.

Louis. Missouri. The serum angiotensin converting enzyme (ACE)

levels were measured as previously described (20) utiliz-

ing hippuryl-L-histidyl-L-leucine as a substrate and the

formation of free hippuric acid by the action of ACE

quantitated as a measure of enzyme activity. One unit

of ACE activity is defined as the nanomoles hippuric acid formed per minute at 37°C under standard assay conditions.

Determination of ibuprofen in plasma

Blood samples were drawn into heparinized tubes at specified time intervals. Plasma was obtained following

centrifugation and was kept frozen at -79°C until analysis.

The Biopharmaceutical Analysis Department at Hazelton

Laboratories America, Inc. (HLA), Madison, Wisconsin has determined the ibuprofen concentrations in baboon

plasma samples by the use of ‘High Pressure Liquid Chromatographic Method’. Briefly’. Briefly, the method

involved extraction of ibuprofen and flurbiprofen

(internal standard) with butyl chloride from plasma made acidic with hydrochloric acid. The samples were

evaporated to dryness, reconstituted in mobile phase

and chromatographed under isocratic conditions with separation on a C,X column. An ultraviolet detector was used for quantitation.

Statistical analysis

Data reduction and statistical analysis was performed using the Statistical Analysis System (Cary, North Caro- lina. USA). First. analysis of variance was performed

to identify the presence of significant differences and the Duncan’s multiple range test for further analysis of the data within groups in the treated groups only. The

\tudent t-test was utilized for unpaired data. Probability of 0.05 or lesb was considered to be significant. All

dara were expressed as mean values +. SEM except for the 2 animals in the vehicle control group. Nonhuman primates are very valuable, difficult to obtain and are expensive. Because of these reasons, 2 animals were studied as vehicle controls so as to establish what the normal pattern will be and to recognize substantial differences from the experimental group. We felt the

data obtained from 2 animals is not appropriate to be

used in statistical analysis. The mean values are provided

for comparison.

Survival studies

Following completion of the study, the incisions were

closed and the animals were returned to their cages. Antibiotics were not routinely given either pre or

post-operatively. The baboons were carefully monitored

during the post-operative period and up to 2 weeks thereafter. Those that had survived for 14 days were taken as permanent survivors.

RESULTS

In the bolus group there were no significant changes in

the mean aortic pressure. In the infusion group, signifi-

cant decrease occurred at 18 and 24 h (p < 0.05), repre- senting a decrease of 18 and 11 mmHg respectively, as

compared to the baseline value. Central venous pressure was well maintained and there was mild tachycardia

but these changes were not significantly different. The results are presented in Figure 1. Renal blood flow and

renal resistance showed no significant changes within

the groups and differences were observed (p < 0.05) between the treated groups only at 6 h during the study

period (Fig. 2).

Serum glucose levels in the treated and vehicle control animals showed individual variations during the

course of the experiment. Serum urea nitrogen levels

. ..c1

0 1 6 12 16 24

TIME IN HOURS

Fig. 1 The effects of vehicle alone (control) or imennittent tbolus)

and continuous administration (mfuaion) otibuprofen on mean aortic pressure (MAP). central venous pressure (CVP). and heart rate (HR).

Values are mean k SEM. Difference\ from baselme value (time 01: * = p < 0.05.


- BOLUS

0 1 6 12 18 24

TIME IN HOURS

Fig. 2 Changes in the renal artery flow and renal resistance following the administration of vehicle alone (control) or intermittent (bolus) and continuous administration (infusion) of ibuprofen. Values are the mean f SEM. Differences between bolus and infusion groups: t = p < 0.05.

decreased progressively in all groups studied and statisti-

cal difference was observed only in the infusion group

at 24 h (p < 0.05). Serum creatinine levels however showed no such changes. Plasma sodium levels were

within normal limits with the exception of a modest increase at 18 and 24 h in the infusion group (p < 0.05).

In contrast to this, potassium levels decreased (p < 0.05) only in the bolus group as early as 6 h into the

experiment. Serum osmolality however, remained stable

during the course of the experiment in all groups. The

data is presented in Table 1. Arterial PO* was well maintained but PC02 levels

showed a tendency to decrease in all groups. Although arterial pH increased in all groups significant differences

occurred only in the bolus group (Fig. 3). There were no appreciable changes in hematocrit and platelet count

either within the groups or between the groups. White cell count showed a tendency to increase in the bolus

Table 1 Blood chemistry and electrolyte levels following intermittent (bolus) or continuous administration (infusion) of ibuprofen and vehicle alone (control)

Parameter Group 0 Time in hours

6 12 18 24

Bun

(mg/dl)

Serum creatinine

(mg/dl)

Serum osmolality

(mGsm/kg H,O)

Serum glucose

(mg/df)

Plasma sodium (mEq/L)

Plasma potassium

(mEoIL)

Bolus 11.8? 1.4 infusion 12.5 f 1.5 control 14.4

Bolus infusion control

0.56 k 0.08 0.77 * 0.14 0.84


297.3 + 2.4 290.0 f 2.3 292.5


80.0 + 3.0 81.0f4.6 109.0

Bolus infusion

146.6 f 1.0 146.5 f 0.5 147.0


3.64 f 0.04 3.39 f 0.20 3.13

I I .6 Yc I .2 10.9 f 1 .o 12.4

0.57 ? 0.08 0.73*0.11 0.7 I

297.0 + 1.7 293.0 ?r 2.0 294.0

85.0 + 10.6 98.5 f 4.8 102.0

147.3 f 0.6 147.6 f 0.5 145.1

3.19 f 0.08* 3.20 + 0.22 3.57

9.9 i 1.9 10.4f I.1 Il.3

0.54 + 0.06 0.76 * 0.17 0.68

296.5 f 2.3 293.0 f 3.3 295.5

104.5 + 11.5 114.8 f 5.3 117.0

148.5 f 2.0 147.5 f 0.7 145.7

3.07 + 0.11* 3.20? 0.28 3.76

9.3 I!I 1.6 9.7 * 1.1 9. I

0.53 ?z 0.08 1.17?0.48 0.74

297.3 + 3.1 296.3 + 3.1 300.0

111.5f20.8 97.3 i 2.4 141.5

148.3 * 2.8 150.6 f 0.9* 147.1

3.22 + 0.20* 3.32 k 0.25 3.56

9.4? 1.8 8.7 ? 0.7* 6.9

0.57 f 0.13 0.72 f 0.14 0.60

297.8 f 3.9 297.3 + 5.9 294.0

123.5 & 16.4 96.0 k 0.7 98.5

147.9 + 2.8 150.4 + I .4* 145.9

3.20 + 0.17* 3.44+0.16 3.51

Either vehicle or ibuprofen was given at time 0. Values are mean + SEM. Differences from baseline value (time 0) * p < 0.05.

Renal Effects of Intermittent Versus Continuous Infusion of Ibuprofen in the Primate 253 -___

N _ ‘20 0,” tU E 100

PE 80

60

0 6 12 18 24

TIME IN HOURS

Fig. 3 The effects of vehicle alone (control) or intermittent

(bolus) and continuous administration (infusion) of ibuprofen on

arterial PO, iPa0,). arterial PCOz (PaCO?). and pH. Values are mean i SEM. Differences from baseline value (time 0): * = p < 0.05.

group, whereas in the other two groups the opposite trend was observed (Fig. 4).

Urinary output was well maintained in the bolus

group with a tendency to decrease in the infusion group bur these changes were not significantly different within

the groups as compared to the baseline value or between the groups. Creatinine clearance and sodium reabsorp-

tion also showed no significant changes (Table 2). Plasma renin activity did not change significantly

either within the groups or between the groups when

treated with ibuprofen. In the control group, however,

the values decreased from a mean baseline value of 9.95 to 2.3 ng/ml/hr at 24 h. Serum levels of angiotensin

converting enzyme showed a tendency to decrease

but were not significantly different. Plasma levels of

0 6 12 18 24

TIME IN HOURS

Fig. 4 The effects of vehicle alone (control) or intermittent

(bolus) and continuous administration (infusion) nf ibuprofen on

some hematologic parameters.

Values arc mean + SEM.

ibuprofen tug/ml), as expected. were undetectable in the

pre-infusion samples and in the control group. In the

treated groups, the serum concentration was relatively similar during the first hour. The differences began to

emerge after this, with the infusion group showing steady

state values during the course of the experiment (Table 3). All of the animals survived the procedure and the

recovery was uneventful.

DISCUSSION

Nonsteroidal antiinflammatory drugs are widely used in

clinical practice for the treatment of various rheumatic

disorders, musculoskeletal pain and dysmenorrhea.

Table 2 The effects of vehicle alone (control) or intermittent (bolus) and continuous admmistration (infusion) of ibuprofen on renal function .____

Time in hours

Paramcler Group 0 6 I2 I8 ?J -____

lrine Bolus 0.177 k .006 0.236 k ,056 0.226 2 .04 I 0.233 i- ,050 0.167 + ,036

wtput infusion 0.2 I8 + ,084 0.176 + ,014 0. I77 + ,055 0. I60 k ,035 (1.177 IL .OOY

(ml,min) control 0. I I3 0. I39 0.2 Ii 0.27 I 0.277

Sodwm Bolu?. 99.6 + .I.5 9Y.4 * .2 I 9Y.7 * .2Y 99.1 k .3 I 09.4 ?r 0. I

reab~orplion infusion YY.6 * I2 99.7+ .I4 YY.7 + .0x 99.x * .05 ‘W7 I 0. I (‘ii) control 99.9 99.8 YY.3 Y8.Y YY. I

Creatimne Bolus 35.9 f 4.2 30.1 + 4.7 3 I .8 * 2.7 39.x + 10.4 26.5 I? Y.0

clearance infusion 32.7 IL 9.3 28.4 k 2. I 2Y.4 t 4.x 26.4 i- 6.3 20.3 2.0 +

(ml/min b control 25.0 26.6 25.5 26.5 12.2

Either vehicle or ibuprofen wa\ given at time 0. Values are mean + SEM.


Table 3 The effects of vehicle alone (control) or intermittent (bolus) and continuous administration (infusion) of ibuprofen

Time in hours Parameter Group 0 1 6 12 18 24

PRA Bolus 3.68 + 0.54 _ 4.38 !c 1.21 5.05 If- 1.80 4.95 f 1.49 4.60 f 2.04 (ngAI/mW infusion 5.20 f 0.74 - 5.95 * 1.21 4.50 I? 0.44 4.83 + 0.27 4.75 * 1.02

control 9.95 _ 3.25 6.40 . 2.90 2.30

ACE Bolus 14.8 f 0.6 _ 14.5 f 1.5 13.1 f 0.6 10.4 f 0.6 11.1 kO.7 (units/ml) infusion 11.9 + 1.5 _ 9.9 * 2.2 10.7 f 1.2 10.1 k 0.7 9.1 f 1.0

control 15.5 _ 13.0 9.4 11.4 12.2

Plasma Bolus < 0.5 29.8 LIZ 3.7 1.7 + 0.5 2.2 k 0.4 2.6 f 0.6 2.98 f 0.6 ibuprofen infusion < 0.5 37.4 + 5.5 15.7 * 1.5 15.6 f 1.5 14.6 f 0.7 14.0 IL 0.7 Wg/ml) control < 0.5 < 0.5 < 0.5 < 0.5 < 0.5 < 0.5

Either vehicle or ibuprofen was given at time 0. Values are mean f SEM. PRA. plasma renin activity: ACE, angiotensin converting enzyme.

These are capable of causing drug induced renal insuffi-

ciency and on occasion may lead to significant nephro-

toxicity. Several mechanisms have been suggested (4) for the renal effects including allergic interstitial

nephritis, impaired renin secretion, increased tubular

reabsorption of sodium and water, and decreased production of vasodilatory prostanoids. Ibuprofen, a propionic

acid derivative is a commonly used NSAID and is primarily excreted by the kidney. Literature review clearly

indicates that patients with preexisting renal and cardiac

disease are at greater risk, but a single large dose of ibuprofen can also cause oliguric renal failure in the

absence of any underlying disease (21). In order to further

elucidate the effects of ibuprofen given intravenously we

studied the differences between the continuous and intermittent administration in the baboon over a 24-h period.

Arterial pressures were maintained at a stable level

with significant decrease occurring only in the infusion

group towards the end of the experiment. This may not be related to a decrease in venous return because the central venous pressure was not significantly different

from the baseline value. When 12.5 mg/kg of ibuprofen

was used as a treatment in endotoxic shock (22), a

significant increase in mean arterial pressure occurred

and this was directly related to an increase in systemic vascular resistance but not cardiac output. In our study

renal blood flow showed a tendency to decrease as

the experiment progressed but showed statistically no significant differences except at one point in time. As a reflection of pressure/flow changes, renal resistance

was significantly different at similar time interval between the treated groups. Although there were no

statistically significant differences, the urinary output showed a tendency to decrease in the group infused with ibuprofen but not in the bolus and control groups. Despite the time dependent variabilities, significant changes were not observed either in creatinine clearance or in sodium reabsorption, suggestive of normal renal function. It should be pointed out, however, that in one of the control animals, diuresis was apparent and as a reflection of this, creatinine clearance also increased, with sodium reabsorption decreasing from a mean pre-infusion value of 99.9% to 99.1% at 24 h. In

a study using dogs injected with 13 mg/kg of ibuprofen (23) a significant decrease in both urine flow and

sodium excretion was observed 45 min following the

treatment. Ibuprofen treatment also decreased the total renal blood flow and the rate of prostaglandin EZ excretion without any significant differences in the regional

renal blood flows in the treated and untreated animals.

In a study conducted in conscious dogs (24) none of the NSAIDs, including ibuprofen affected renal blood

flow, resting blood pressure or heart rate. In healthy

men and women (25, 26) treated with therapeutic doses of ibuprofen there was no substantial renal impairment

despite a decrease in renal prostaglandin synthesis. In patients with impairment of renal function however cau-

tion should be exercised in treating with NSAIDs (26).

Plasma renin activity did not show significant differ-

ences in the treated groups but in the control animals, a decrease was observed during the course of the experiment. It has been reported that prostaglandin directly

stimulates the release of renin in healthy subjects (27) and its suppression in the ibuprofen treated animals

did not appear to influence the plasma renin activity

to a significant degree. Patients with mild renal impairment treated with ibuprofen however showed a signifi-

cant reduction in plasma renin activity (26) suggesting variability in activity in functionally healthy vs. impaired

kidney. In the present study we measured ACE activity in the

serum following either a continuous infusion or bolus

injection of ibuprofen as well as in the control animals.

The values tended to decrease over time in all groups. Activity of ACE is recognized as a specific indicator of pulmonary endothelial integrity (28). It is localized

principally on the luminal surface of the capillary endothelium and the endothelial damage results in the release of ACE into the circulation. Studies in the sheep following the administration of indomethacin with or without elevation in the left atria1 pressure did not

elicit any significant changes in the ACE activity either in the serum or lymph (29). Our observation in the baboon with ibuprofen treatment is similar to that has been observed in the sheep and changes in pulmonary vascular permeability secondary to a loss of endothelial

Renal Effects of Intermittent Versus Continuous Infusion of Ibuprofen in the Primate 255

integrity did not appear to play a part as evidenced by

ACE levels. Circulating levels of ibuprofen measured immediately

prior to the bolus injection given at 6-h intervals showed a steady state. Although timing may not be as important

in the group receiving continuous infusion a steady

state was clearly achieved by 4 h and continued at that state during the 24-h study period. To accurately gauge

the steady state serum concentration of a drug, the blood

sample needs to be obtained at strategic times during

the course of administration so as to ensure that the absorption is complete and a steady state in vivo equili-

bration has been achieved.

Arterial PO, remained relatively stable in all groups

with a tendency for PC02 to decrease over time. Recent studies (30) suggest that cyclooxygenase inhibitors

increases pulmonary vascular resistance and capillary

pressure in a dose related manner in the canine lung

lobe. It is important to recognize that segmental vascular resistance at equimolar concentrations differ, with

smallest effects being observed with ibuprofen. Whether

these effects will be similar in the baboon cannot be

answered but it seems apparent that the dose level we

have used did not adversely effect the pulmonary function as it relates to blood gas exchange. The increase

in arterial pH is probably a reflection of decreased

PC’O, as a result of hyperventilation. The adverse effects of non-steroidal anti-inflammatory

drugs on renal function has been attributed partly

to inhibition of renal synthesis of vasodilatory pro-

staglandins. In healthy women, as well as patients with mild renal impairment treated with ibuprofen, a pro-

found suppression of urinary prostaglandin E2 and

h-keto-prostaglandin F,, excretion was observed (26).

Renal cortical events in human beings is thought to be

controlled by prostacyclin synthesized in glomeruli. The

dependence of renal function on cyclooxygenase may be a more common finding and may reflect intrarenal as

well as extrarenal mechanisms especially in conjunction with compromised renal function. Similar suppression

of renal prostacyclin synthesis may not be functionally significant in a healthy individual. Ibuprofen associated

nephropathies are usually reversible after discontinua-

tion of the drug but this may not occur in some

parients. Although NSAIDs are effective inhibitors of

prostaglandin synthesis they may not totally suppress basal prostaglandin production and particularly in target

tissues the production may be reduced but may not cease completely (31). There is general agreement, however, that NSAlDs share some common pharmacologic effects In spite of their diverse chemical structure and are

effective inhibitors of prostaglandin synthesis.

‘This study in the anesthetized baboon demonstrates that ibuprofen in the dose levels administered intravenously gives some variability in the parameters observed. These effects are either mild or insignificant. While it is safe to assume that treatment with ibuprofen is safe in ;i normal healthy state. caution should be exercised when

certain risk factors such as underlying renal disease, ne-

phrotoxic drug therapy or concomitant diuretic therapy

are present (32).

Acknowledgement

This study was supported in part by the Upjohn Company. Kalamazoo. MI.

We gratefully acknowledge the technical assistance of Eric Spaziani, William Fay and Lloyd Graham.

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renal effects of intermittent versus continuous infusion of ibuprofen in the primate

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