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Urinary Prostaglandin E2 in Acute Bacterial Cystitis
0022-5347 /80/1244-0455$02.00/0 Vol. 124, Octobe,-
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1980 by The Williams & Wilkins. Co.
URINARY PROSTAGLANDIN E2 IN ACUTE BACTERIAL CYSTITIS AMICUR FARKAS,* DAVID ALAJEM, SAMUEL DEKEL
AND
IZHAK BINDERMAN
From the Department of Urology, Hard Tissues Research Unit, Municipal Governmental Medical Center, Ichilov Hospital and Sackler School of Medicine, Tel-Aviv, Israel
ABSTRACT
The levels of prostaglandin E2 were studied in the urine of 14 female patients with acute bacterial cystitis. Ten healthy female students served as a control group. Results indicated a significant increase of urinary prostaglandin levels with a consistent relationship to the onset and duration of the clinical symptoms. Observations during the last decade have demonstrated that the local release or administration of prostaglandi.ns causes classical signs of inflammation, such as erythema, 1• 2 edema3- 5 and pain. 6• 7 Acute bacterial cystitis is a frequent finding among otherwise healthy female subjects. The onset of symptoms, ,u,c,wu.rn,i,; suprapubic pain, dysuria, urinary urgency and frequency and, eventually, hematuria, is quite dramatic. However, the severe discomfort disappears even without treatment if no underlying obstructive or other uropathy exists. This inflammatory process, with an onset and duration that can be determined easily by subjective symptoms and objective bacteriuria,
cystitis was verified by urinalysis and urine cultures
n<:m.,Ju.i<
> 105 colonies per cc Escherichia coli. The patients received no treatment before hospitalization and remained untreated during the study period. In addition to the initial urinalysis daily urine cultures and samples were obtained from every patient during 10 consecutive days in the following manner. The women were asked to report to the laboratory at 8 a.m., after 8 hours of fluid intake restrictions. They were asked to empty the bladder on arrival and then were given a constant amount of 400 ml. of fluid orally during a shmt interval (5 to 7 minutes). Urine samples for the study were
30,000
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22,000
E
Control
0,
Patients
0.
ci
a.:
"'C 14,000 u C
"' 12,000 Cl)
-"' '"
~ a..
6,000
2,000 0
2
3
5
4
6
7
8
9
10
Days
Fw. 1. Prostaglandin E2 levels in urine of study and control groups, expressed in picog.rams per cc urine. Significant p <0.01
obtained 30 and 60 minutes thereafter. A concurrent contrnl group of 10 volunteer female student nurses provided urine samples in the same manner. The method ensured a constant urine concentration that was checked by urine osmolarity and urine creatinine concentrations. The pH was determined i.n every sample and those in which the pH was not within the range of 6 to 6.5 were excluded from the study. The urine samples were centrifuged immediately at OC, followed by ether extraction at pH 6 to 6.5. At such a pH arachidonic acid, if present, is extracted in the discarded ether phase, while prostaglandins remain dissolved in the retained aqueous phase.
can serve as a model to study urine prostaglandin levels and their correlation to the symptoms and signs of the acute disease. MATERIAL AND METHODS
We studied 14 women, ranging in age from 18 to 40 years, who presented with acute cystitis at the primary care clinic of the hospital. The duration of symptoms at the time of presentation ranged from 4 to 8 hours. The diagnosis of acute bacterial Accepted for publication January 18, 1980. * Current address: Shaare Zedek Medical Center, Jerusalem, Israel. 455
456
FARKAS AND ASSOCIATES
Prostaglandin E2 levels were determined by the radioimmunoassay technique described by Bauminger and associates using rabbit sera sensitized with prostaglandin E2 and tritium-labeled prostaglandin E2. 8 The crossed reaction of the antiserum was moderate (<10 per cent) with prostaglandins El, Al, A2, Bl and B2 and negligible with prostaglandins of the F type (<0.5 per cent) and with arachidonic acid (<0.01 per cent). Two separate assays were done on each urine sample at different dilutions, 0.0025 and 0.01 ml. urine diluted to a volume of 0.4 ml. with buffer tris solution at pH 7. The results are expressed in picograms of prostaglandin E2 per ml. urine. The results were statistically analyzed using Student's t test and significance was defined as p <0.01.
40,000
30,
. C
::, E
~ 20, <>.
·-
RESULTS
Urinary prostaglandin E2 levels were monitored during 10 consecutive days in 14 patients with acute bacterial cystitis and in 10 healthy female students serving as a control group (fig. 1). The curves demonstrated clearly a significant elevation of urinary prostaglandin E2 during the period of the acute disease compared to the control group and to each single patient's values during the asymptomatic period. Of the 14 patients 12 had a classical course of acute bacterial cystitis. They experienced relief of the severe discomfort within 24 to 48 hours and the initial cultures, which were all positive, became sterile within 48 to 72 hours. The mean prostaglandin E2 levels in the urine were slightly elevated on the initial day and reached a sharp significant peak during days 2 and 3 and then declined again to normal values. Figure 2 demonstrates a typical pattern of urinary prostaglandin E2 levels in this group of patients. Two patients experienced a recurrence of clinical symptoms with positive urine cultures within the period of the study (on days 6 and 7). Figure 3 depicts a second peak of urinary
10,0
2,000
0
2
3
4
5
6
7
8
9
10
11
12
Days
FIG. 3. Correlation of urinary prostaglandin levels and clinical course of 34-year-old patient. a, onset of severe clinical symptoms, with positive urine culture. b, partial relief of symptoms. c, complete relief of symptoms. d, severe symptoms recurred, urine culture still is positive. e, relief of symptoms. f, complete relief of symptoms, urine culture is sterile.
prostaglandin E2 levels corresponding with the recurrence of the clinical symptoms.
40,000 COMMENT
A significant elevation of prostaglandin E2 in the urine of patients with acute bacterial cystitis is demonstrated. The correlation of this elevation to the clinical symptomatology also is seen. This correlation is most evident in the 2 cases in which clinical symptoms recurred. Of major interest was the fact that the peak levels of prostaglandin E2 occurred 1 to 2 days after the disappearance of the clinical symptoms. Prostaglandins are synthesized in small quantities by human bladder muscle strips and are most probably involved in maintaining their normal tonus. 9 • 10 However, their exact site of synthesis and the subsequent relationship to lower urinary tract symptoms remain to be clarified. The potential beneficial clinical effects of prostaglandin synthetase inhibitors, such as salicylates and indomethacin, in mitigating the severe discomfort associated with cystitis need to be evaluated further and studies to these ends are now in progress in our laboratory.
30,000
., C:
::,
E
";;;- 20,000 C.
c:.?
a:
REFERENCES
10,00
2,000
0
2
3
4
5
6
7
8
9
10
Days
FIG. 2. Correlation of urinary prostaglandin levels and clinical course of 28-year-old patient. a, onset of severe clinical symptoms, with positive urine culture. b, partial relief of symptoms. c, complete relief of symptoms. d, urine culture is sterile.
1. Solomon, L. M., Juhlin, L. and Kirschenbaum, M. B.: Prostaglandin on cutaneous vasculature. J. Invest. Derm., 51: 280, 1968. 2. Juhlin, L. and Michaelsson, G.: Cutaneous vascular reactions to prostaglandins in healthy subjects and in patients with urticaria and atopic dermatitis. Acta Dermatovener., 49: 251, 1969. 3. Crunkhorn, P. and Willis, A. L.: Actions and interactions of prostaglandins administered intradermally in rat and in man. Brit. J. Pharmacol., 47: 216, 1969. 4. Kalley, G. and Winer, R.: Prostaglandin El: a potential mediator of the inflammatory response. Ann. N.Y. Acad. Sci., 180: 338, 1971. 5. Moncada, S., Ferriera, S. H. and Vane, J. R.: Prostaglandins, aspirin-like drugs and the edema of inflammation. Nature, 246: 217, 1973. 6. Ferriera, S. H., Moncada, S. and Vane, J. R.: Further experiments
URINARY PROSTAGLANDIN E2 IN ACUTE BACTERIAL CYSTITIS
to establish the analgesic action of aspirin-like drugs depends on the inhibition of prostaglandin biosynthesis. Brit. J. Phannacol., 47: 629P, 1973. 7. Moncada, S., Ferriera, S. H. and Vane, J. R.: Inhibition of prostaglandin biosynthesis as the mechanism of analgesia of aspirinlike drugs in the dog knee joint. Eur. J. Pharmacol., Sll: 250, 1975. 8 . .u11.uuuu.~e1 S., Zor, U. and Lindner, H. R.: Radioimmunological prostaglandin synthetase activity. Prostaglandins, 4:
4-5?
313, 1973.
9. Bultitude, M. I., Hills, N. H. and Shuttleworth, K E. D.: ClinicsJ. and experimental studies on the action of prostaglandins and their synthesis inhibitors on detrusor muscle in vit:ro and in vivo. Brit. J. Urol., 48: 631, 1976. 10. Abrams, P.H., Sykes, J. A. C., Rose, A. J. and Rogers, A. F.: The synthesis and release of prostaglandins by human urinary bladder muscle in vitro. Invest. Urol., Hil: 346, 1979.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1980 by The Williams & Wilkins. Co.
URINARY PROSTAGLANDIN E2 IN ACUTE BACTERIAL CYSTITIS AMICUR FARKAS,* DAVID ALAJEM, SAMUEL DEKEL
AND
IZHAK BINDERMAN
From the Department of Urology, Hard Tissues Research Unit, Municipal Governmental Medical Center, Ichilov Hospital and Sackler School of Medicine, Tel-Aviv, Israel
ABSTRACT
The levels of prostaglandin E2 were studied in the urine of 14 female patients with acute bacterial cystitis. Ten healthy female students served as a control group. Results indicated a significant increase of urinary prostaglandin levels with a consistent relationship to the onset and duration of the clinical symptoms. Observations during the last decade have demonstrated that the local release or administration of prostaglandi.ns causes classical signs of inflammation, such as erythema, 1• 2 edema3- 5 and pain. 6• 7 Acute bacterial cystitis is a frequent finding among otherwise healthy female subjects. The onset of symptoms, ,u,c,wu.rn,i,; suprapubic pain, dysuria, urinary urgency and frequency and, eventually, hematuria, is quite dramatic. However, the severe discomfort disappears even without treatment if no underlying obstructive or other uropathy exists. This inflammatory process, with an onset and duration that can be determined easily by subjective symptoms and objective bacteriuria,
cystitis was verified by urinalysis and urine cultures
n<:m.,Ju.i<
> 105 colonies per cc Escherichia coli. The patients received no treatment before hospitalization and remained untreated during the study period. In addition to the initial urinalysis daily urine cultures and samples were obtained from every patient during 10 consecutive days in the following manner. The women were asked to report to the laboratory at 8 a.m., after 8 hours of fluid intake restrictions. They were asked to empty the bladder on arrival and then were given a constant amount of 400 ml. of fluid orally during a shmt interval (5 to 7 minutes). Urine samples for the study were
30,000
:)
22,000
E
Control
0,
Patients
0.
ci
a.:
"'C 14,000 u C
"' 12,000 Cl)
-"' '"
~ a..
6,000
2,000 0
2
3
5
4
6
7
8
9
10
Days
Fw. 1. Prostaglandin E2 levels in urine of study and control groups, expressed in picog.rams per cc urine. Significant p <0.01
obtained 30 and 60 minutes thereafter. A concurrent contrnl group of 10 volunteer female student nurses provided urine samples in the same manner. The method ensured a constant urine concentration that was checked by urine osmolarity and urine creatinine concentrations. The pH was determined i.n every sample and those in which the pH was not within the range of 6 to 6.5 were excluded from the study. The urine samples were centrifuged immediately at OC, followed by ether extraction at pH 6 to 6.5. At such a pH arachidonic acid, if present, is extracted in the discarded ether phase, while prostaglandins remain dissolved in the retained aqueous phase.
can serve as a model to study urine prostaglandin levels and their correlation to the symptoms and signs of the acute disease. MATERIAL AND METHODS
We studied 14 women, ranging in age from 18 to 40 years, who presented with acute cystitis at the primary care clinic of the hospital. The duration of symptoms at the time of presentation ranged from 4 to 8 hours. The diagnosis of acute bacterial Accepted for publication January 18, 1980. * Current address: Shaare Zedek Medical Center, Jerusalem, Israel. 455
456
FARKAS AND ASSOCIATES
Prostaglandin E2 levels were determined by the radioimmunoassay technique described by Bauminger and associates using rabbit sera sensitized with prostaglandin E2 and tritium-labeled prostaglandin E2. 8 The crossed reaction of the antiserum was moderate (<10 per cent) with prostaglandins El, Al, A2, Bl and B2 and negligible with prostaglandins of the F type (<0.5 per cent) and with arachidonic acid (<0.01 per cent). Two separate assays were done on each urine sample at different dilutions, 0.0025 and 0.01 ml. urine diluted to a volume of 0.4 ml. with buffer tris solution at pH 7. The results are expressed in picograms of prostaglandin E2 per ml. urine. The results were statistically analyzed using Student's t test and significance was defined as p <0.01.
40,000
30,
. C
::, E
~ 20, <>.
·-
RESULTS
Urinary prostaglandin E2 levels were monitored during 10 consecutive days in 14 patients with acute bacterial cystitis and in 10 healthy female students serving as a control group (fig. 1). The curves demonstrated clearly a significant elevation of urinary prostaglandin E2 during the period of the acute disease compared to the control group and to each single patient's values during the asymptomatic period. Of the 14 patients 12 had a classical course of acute bacterial cystitis. They experienced relief of the severe discomfort within 24 to 48 hours and the initial cultures, which were all positive, became sterile within 48 to 72 hours. The mean prostaglandin E2 levels in the urine were slightly elevated on the initial day and reached a sharp significant peak during days 2 and 3 and then declined again to normal values. Figure 2 demonstrates a typical pattern of urinary prostaglandin E2 levels in this group of patients. Two patients experienced a recurrence of clinical symptoms with positive urine cultures within the period of the study (on days 6 and 7). Figure 3 depicts a second peak of urinary
10,0
2,000
0
2
3
4
5
6
7
8
9
10
11
12
Days
FIG. 3. Correlation of urinary prostaglandin levels and clinical course of 34-year-old patient. a, onset of severe clinical symptoms, with positive urine culture. b, partial relief of symptoms. c, complete relief of symptoms. d, severe symptoms recurred, urine culture still is positive. e, relief of symptoms. f, complete relief of symptoms, urine culture is sterile.
prostaglandin E2 levels corresponding with the recurrence of the clinical symptoms.
40,000 COMMENT
A significant elevation of prostaglandin E2 in the urine of patients with acute bacterial cystitis is demonstrated. The correlation of this elevation to the clinical symptomatology also is seen. This correlation is most evident in the 2 cases in which clinical symptoms recurred. Of major interest was the fact that the peak levels of prostaglandin E2 occurred 1 to 2 days after the disappearance of the clinical symptoms. Prostaglandins are synthesized in small quantities by human bladder muscle strips and are most probably involved in maintaining their normal tonus. 9 • 10 However, their exact site of synthesis and the subsequent relationship to lower urinary tract symptoms remain to be clarified. The potential beneficial clinical effects of prostaglandin synthetase inhibitors, such as salicylates and indomethacin, in mitigating the severe discomfort associated with cystitis need to be evaluated further and studies to these ends are now in progress in our laboratory.
30,000
., C:
::,
E
";;;- 20,000 C.
c:.?
a:
REFERENCES
10,00
2,000
0
2
3
4
5
6
7
8
9
10
Days
FIG. 2. Correlation of urinary prostaglandin levels and clinical course of 28-year-old patient. a, onset of severe clinical symptoms, with positive urine culture. b, partial relief of symptoms. c, complete relief of symptoms. d, urine culture is sterile.
1. Solomon, L. M., Juhlin, L. and Kirschenbaum, M. B.: Prostaglandin on cutaneous vasculature. J. Invest. Derm., 51: 280, 1968. 2. Juhlin, L. and Michaelsson, G.: Cutaneous vascular reactions to prostaglandins in healthy subjects and in patients with urticaria and atopic dermatitis. Acta Dermatovener., 49: 251, 1969. 3. Crunkhorn, P. and Willis, A. L.: Actions and interactions of prostaglandins administered intradermally in rat and in man. Brit. J. Pharmacol., 47: 216, 1969. 4. Kalley, G. and Winer, R.: Prostaglandin El: a potential mediator of the inflammatory response. Ann. N.Y. Acad. Sci., 180: 338, 1971. 5. Moncada, S., Ferriera, S. H. and Vane, J. R.: Prostaglandins, aspirin-like drugs and the edema of inflammation. Nature, 246: 217, 1973. 6. Ferriera, S. H., Moncada, S. and Vane, J. R.: Further experiments
URINARY PROSTAGLANDIN E2 IN ACUTE BACTERIAL CYSTITIS
to establish the analgesic action of aspirin-like drugs depends on the inhibition of prostaglandin biosynthesis. Brit. J. Phannacol., 47: 629P, 1973. 7. Moncada, S., Ferriera, S. H. and Vane, J. R.: Inhibition of prostaglandin biosynthesis as the mechanism of analgesia of aspirinlike drugs in the dog knee joint. Eur. J. Pharmacol., Sll: 250, 1975. 8 . .u11.uuuu.~e1 S., Zor, U. and Lindner, H. R.: Radioimmunological prostaglandin synthetase activity. Prostaglandins, 4:
4-5?
313, 1973.
9. Bultitude, M. I., Hills, N. H. and Shuttleworth, K E. D.: ClinicsJ. and experimental studies on the action of prostaglandins and their synthesis inhibitors on detrusor muscle in vit:ro and in vivo. Brit. J. Urol., 48: 631, 1976. 10. Abrams, P.H., Sykes, J. A. C., Rose, A. J. and Rogers, A. F.: The synthesis and release of prostaglandins by human urinary bladder muscle in vitro. Invest. Urol., Hil: 346, 1979.