Long term ‘marine diet’ in Eskimos is not associated with altered urinary excretion of total tetranor prostaglandin metabolites

The total urinary excretion of tetranor prostaglandin metabolites, measured as tetranorprostanedioic acid (TPD), was quantified in traditionally living Greenland Eskimos (E) and compared with that in Caucasian Danes (D). TPD excretion (μg/24h) was not significantly different between both groups, neither for males (331 ± 62.4 (E) vs. 331 ± 25.7 (D), mean ± SEM, n = 9 and 10) nor for females (190 ± 31.7 (E) vs. 264 ± 27.4 (D), n = 11 and 10, P₂ > 0.05). Since urinary prostaglandin metabolites are thought to reflect the total prostaglandin turnover in vivo, these results suggest that a long-term intake of relatively large amounts of polyunsaturated fatty acids of the (n-3) family does not alter total prostaglandin turnover in vivo. This is in contrast to stimulated prostanoid formation in vitro, and thus suggests a different regulatory role of dietary and tissue fatty acids for ‘stimulated’ and ‘basal’ prostaglandin production.     

Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig

Infusion of norephinephrine (NE) (1 – 3 μg/ml/min) into the isolated mesenteric vascular preparation of rabbit resulted in a rise in perfusion pressure, which was associated with the release of a prostaglandin E-like substance (PGE) at a concentration of 2.81 ± 0.65 ng/ml in terms of PGE₂. Indomethacin (3 μg/ml) abolished the NE-induced release of PGE. Arachidonic acid (0.2 μg/ml) in the presence of indomethacin did not restore the NE-induced release of PGE. Hydrocortisone (10 – 30 μg/ml) and dexamethasone (2 – 5 μg/ml) also inhibited the NE-induced release of PGE. The inhibitory action of both corticosteroids was abolished by arachidonic acid (0.2 μg/ml). Antigen-induced release of a prostaglandin-like substance(PGs) (43.1 ± 3.8 ng/ml in terms of PGE₂ and a rabbit aorta contracting substance (RCS) from perfused lungs of sensitized guinea pigs was completely abolished by indomethacin (5 μg/ml) or by hydrocortisone (100 μg/ml). Indomethacin, however, increased histamine release up to 280% of the control level, which was 470 ± 54 ng/ml, while hydrocortisone diminished histamine release down to 30% of the control level. A superimposed infusion of arachidonic acid (1 μg/ml) into the pulmonary artery reversed the hydrocortisone-induced blockade of the release of RCS and PGs. It may be concluded that corticosteroids neither inhibit prostaglandin synthetase nor influence prostaglandin transport through the membranes but they do impair the availability of the substrate for the enzyme.     

Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig

Infusion of norephinephrine (NE) (1 – 3 μg/ml/min) into the isolated mesenteric vascular preparation of rabbit resulted in a rise in perfusion pressure, which was associated with the release of a prostaglandin E-like substance (PGE) at a concentration of 2.81 ± 0.65 ng/ml in terms of PGE₂. Indomethacin (3 μg/ml) abolished the NE-induced release of PGE. Arachidonic acid (0.2 μg/ml) in the presence of indomethacin did not restore the NE-induced release of PGE. Hydrocortisone (10 – 30 μg/ml) and dexamethasone (2 – 5 μg/ml) also inhibited the NE-induced release of PGE. The inhibitory action of both corticosteroids was abolished by arachidonic acid (0.2 μg/ml). Antigen-induced release of a prostaglandin-like substance (PGs) (43.1 ± 3.8 ng/ml in terms of PGE₂ and a rabbit aorta contracting substance (RCS) from perfused lungs of sensitized guinea pigs was completely abolished by indomethacin (5 μg/ml) or by hydrocortisone (100 μg/ml). Indomethacin, however, increased histamine release up to 280% of the control level, which was 470 ± 54 ng/ml, while hydrocortisone diminished histamine release down to 30% of the control level. A superimposed infusion of arachidonic acid (1 μg/ml) into the pulmonary artery reversed the hydrocortisone-induced blockade of the release of RCS and PGs. It may be concluded that corticosteroids neither inhibit prostaglandin synthetase nor influence prostaglandin transport through the membranes but they do impair the availability of the substrate for the enzyme.     

Ductus arteriosus: Developmental response to oxygen and indomethacin

It has been suggested that ineffective constriction in response to an increase in PO₂ is the primary cause for delayed closure of the ductus arteriosus in preterm infants. We studied the isometric contractile effects of increased PO₂ and indomethacin on isolated rings of lamb ductus arteriosus from animals of different gestational ages (87 to 147 days, term is 150 days). Rings from animals less than 110 days have a significantly smaller oxygen-induced contraction (2.53 ± .30 g/mm², n = 16) when compared with rings from animals near term (4.59 ± .69 g/mm², n = 9). Oxygen contracted rings from all gestational ages contract further upon addition of 1 μg/ml indomethacin. Rings from animals less than 110 days have a significantly larger indomethacin induced contraction (1.10 ± .17 g/mm², n = 16) than vessels near term (0.52 ± .12 g/mm², n = 9). Inhibition of prostaglandin production in rings less than 110 days results in a total combined oxygen and indomethacin induced tension that is not significantly different from the oxygen or oxygen and indomethacin induced tension developed in rings from animals near term. This is consistent with the hypothesis that, early during gestation, endogenous prostaglandins inhibit the vessel's ability to contract in response to oxygen. These observations are also consistent with the ability of indomethacin to constrict the patient ductus arteriosus in pre-term infants.     

Indomethacin does not potentiate renovascular constriction during hypercapnia in unanesthetized rabbits

The role of prostanoids in regulation of the renal circulation during hypercapnia was examined in unanesthetized rabbits. Renal blood flow (RBF) was determined with 15 μm radioactive microspheres during normocapnia (PaCO₂ 30 mmHg) and hypercapnia (PaCO₂ 60 mmHg), before and after intravenous administration of indomethacin (10 mg/kg) or vehicle (n=6 for each group). Arterial blood pressure was not different among the 4 conditions in each group. RBF was 438±61 and 326 ± 69 (P<0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before indomethacin, and following administration of indomethacin, RBF was 426 ± 59 ml/min per 100 g during normocapnia and 295 ± 60 ml/min per 100 g during hypercapnia (P<0.05). In the vehicle group, RBF was 409±74 and 226±45(P<0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before vehicle; and following administration of vehicle, RBF was 371±46 ml/min per 100 g during normocapnia and 219 ± 50 (P<0.05) per 100 g during hypercapnia. RBF during normocapnia was not affected by administration of indomethacin or vehicle. The successive responses to hypercapnia were not different within the indomethacin and vehicle groups, and the second responses to hypercapnia were not different between the two groups. These findings suggest that prostanoids do not contribute significantly to regulation of the renal circulation during normocapnia and hypercapnia in unanesthetized rabbits.     

Comparison of three subcutaneous modes of prostaglandin F2α administration for pregnancy termination in the hamster

Dose response relationships for pregnancy termination in hamsters following administration of prostaglandin F_2α (PGF_2α by three subcutaneous methods were determined in 526 hamsters. The median effective dose (ED₅₀) for PGF_2α given as a single subcutaneous injection in 500 μl of saline was 22.2 μg. Administration of the prostaglandin with an Alzet® osmotic minipump (subcutaneous insertion for 24 hours) required 1.35 times more PGF_2α (ED₅₀ = 30.0 μg). The least effective method of prenancy termination in the hamster involved administration of PGF_2α by a single subcutaneous injection in 20.4 μl of saline (the same volume delivered by the minipump in 24 hours); the ED₅₀ for this method of administration was 41.3 μg of PGF_2α.     

The effect of 15 (R) 15 methyl prostaglandin E2 on gastric acid secretion in duodenal ulcer patients

The effect of synthetic analogue 15 (R) 15 methyl PGE₂ on basal and pentagastrin stimulated maximal acid output in 24 duodenal ulcer patients has been studied. The prostaglandin analogue in a single oral dose of 150 μg reduced both basal and maximum output. Basal acid output fell from a mean control value of 5.9 ± 1.5 mEq/hr to 2.1 ± 0.6 mEq/hr (p < 0.05) and maximum acid output from 32.1 ± 1.6 mEq/hr to 20.6 mEq/hr (p < 0.001). The volume of gastric secretion did not alter significantly in the basal state but fell significantly in the maximally stimulated state after prostaglandin administration.     

Indomethacin inhibits the uptake of sodium by ovine trophoblastic tissue in vitro

Blastocysts from several species synthesize prostaglandins in vitro, but the exact functions of the prostaglandins are unknown. The purpose of this study was to determine if indomethacin, an inhibitor of prostaglandin synthesis, would inhibit the uptake of ²²sodium ([²²Na]) by ovine trophoblastic tissue. To determine the concentration of indomethacin that would inhibit the synthesis of PGF_2α and 13,14-dihydro-15-keto-PGF_2α (PGFM) by blastocysts, blastocysts were collected from ewes 16 days after mating, sliced into pieces approximately 2 mm in length and incubated for 48 h at 37°C in 2 ml of medium containing either 0, 0.2, 0.4, 0.8 or 1.6 mM of indomethacin. Concentrations of indomethacin mM reduced (P<.01) trophoblastic release (ng/μg DNA) of PGF_2α from

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, reduced PGFM from

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, and inhibited formation of trophoblastic vesicles. In a second experiment, blastocysts were recovered from ewes 16 days after mating and pieces of trophoblast were incubated with [²²Na] and either 0 or 0.4 mM of indomethacin. Indomethacin reduced the uptake of [²²Na], which is an indirect measure of the transport of water across epithelia, from 3680 ± 1118 to 934 ± 248 cpm/μg DNA (P<.03) and prevented formation of trophoblastic vesicles. Prostaglandins produced by ovine blastocysts might be involved in controlling uptake of water, which is essential for expansion of blastocysts.     

Prostaglandin synthesis by enterocyte microsomes of rabbit small intestine

We studied the prostaglandin (PG) synthetic capacity of microsomes of a relatively pure population of rabbit enterocytes and determined ideal conditions for product synthesis. The epithelial cells were freed from the basement membrane by a combination of calcium chelation and mechanical vibration, and 100,000 x g microsomes were prepared. These microsomes were found to synthesize PG from exogenously added arachidonic acid. The ideal conditions for the reaction were a microsomal protein concentration of 1.0 mg/ml, an arachidonic acid concentration of 33 μM, a reaction mixture pH of 8.0 − 9.5 and with epinephrine 1.5 mM added as a cofactor. The product yields increased linearly with time up to 30 min, of incubation and were inhibited by 100 μM indomethacin. Under the above ideal conditions enterocyte microsomes yielded the following products expressed as pmole/mg protein/20 min, incubation: PGF_2α 98±7, PGE₂ 48±9, PGD₂ 28±7, TxB₂ 40±5, 6 Keto PGF_1α 15 ± 6.     

Pregnancy termination with the PGE2-analogue SHB 286

A group of 94 volunteers were treated with PGE₂-analogue SHB 286 at the 12±1 week of pregnancy. Of the 94 gravidas, 78 received a single extraovular dose of 50–200μg (Mean±S.E. 76±7μg) while 16 a short intravenous infusion of 1000–200μg SHB 286. Despite the single treatment and low dose, the success rate was 69% and the instillation-abortion time only 15±1 hours. At 24 hours after treatment even those gravidas who failed to abort (31%) had sufficient cervical dilatation for curettage and thus could be spared from rapid surgical dilatation.Peripheral plasma progesterone and estradiol-17β decreased significantly at 4 hours after treatment in those gravidas who subsequently aborted. After an initial contracture response of the uterus to SHB 286, the cyclic intrauterine pressure evolved gradually. In 4 hours it reached significantly higher levels in those gravidas who subsequently aborted than in those who did not.     

Effect of indomethacin and 7-oxa-13-prostynoic acid on luteinization of transplanted rat ovarian follicles induced by luteinizing hormone and prostaglandin E2

The ability of prostaglandin E₂ (PGE₂) to initiate luteinization was demonstrated using a system of in vitro incubation of ovarian follicles followed by transplantation. Follicles from diestrous rats were incubated with 0.05 to 50 μg/ml PGE₂, 10 μg/ml luteinizing hormone (LH), or alone in Krebs-Ringer bicarbonate buffer plus glucose for 2 hr. Then follicles were transplanted under the kidney capsules of hypophysectomized recipients, with follicles exposed to PGE₂ on one side and those exposed to LH or buffer only on the other side. As determined at autopsy 4 days later and confirmed by histological examination, follicles exposed to PGE₂ at concentrations of 0.5 μg/ml or greater, or to LH, transformed into corpora lutea, but control follicles regressed. Incubation of follicles with LH in the presence of indomethacin, an inhibitor of prostaglandin synthesis, significantly reduced the incidence of luteinization. Prostaglandin E₂ (10 μg/ml) was able to override the inhibition of luteinization by indomethacin (150 μg/ml). The prostaglandin analogue 7-oxa-13-prostynoic acid (100 μg/ml) failed to prevent luteinization in response to either 5 μg/ml LH or 1 μg/ml PGE₂. Results with PGE₂ and with indomethacin suggest a role for prostaglandins in the luteinizing action of LH.We have reported previously that in vitro exposure of diestrous rat follicles to luteinizing hormone (LH) will result in transformation of the follicles to corpora lutea following transplantation under the kidney capsules of hypophysectomized rats. Dibutyryl cyclic AMP (DBC) mimics this effect of LH, and transplants produce progesterone in measurable amounts after both LH and DBC exposure when prolactin is administered in vivo to recipients.Kuehl et al. have suggested that prostaglandins may act as obligatory intermediates in the effect of LH on the ovary, acting between LH and adenylate cyclase. Preliminary results indicated that prostaglandin E₂ (PGE₂) could induce luteinization in our system. The extent of prostaglandin involvement in luteinization was further investigated in this work, using two reported antagonists of prostaglandin action, indomethacin and 7-oxa-13-prostynoic acid. Indomethacin has been found to inhibit synthesis of prostaglandins E₂ and F_2α; 7-oxa-13-prostynoic acid, which acts as a competitive antagonist of prostaglandins, prevented the effect of LH and prostaglandins E₁ and E₂ on cyclic AMP production in mouse ovaries.     

Induction of renin release by exogenous prostaglandins in hyporeninemic hypoaldosteronism

A deficiency in renal prostaglandin synthesis has been proposed as the cause of the syndrome of hyporeninemic hypoaldosteronism. To determine if renin release could be stimulated by pharmacologic infusions of PGA₁, we infused PGA₁ 0.075 to 0.60 μg/kg/min to nine patients with the syndrome. Total renal PGE production as measured by urinary PGE excretion was normal (650 ± 169 vs 400 ± 55 ng/24hr in normal subjects). Renin (PRA) was markedly depressed in all patients despite stimulation with upright posture and furosemide (1.0 ± 0.4 vs 9.3 ± 0.7 ng/ml/hr, p<0.001). But in two patients PGA₁ induced an increase in renin similar to that of normal subjects. PRA increased to a lesser degree in two other patients and plasma aldosterone slightly increased. Five showed no response. Infusions of nitroprusside in doses and duration that mimicked the hypotensive effects of PGA₁ failed to increase PRA or aldosterone. The data suggest that total renal PGE production is normal in patients with the syndrome of hyporeninemic hypoaldosteronism. Although orthostasis, furosemide and nitroprusside do not increase renin, prostaglandin A₁ infusion appears to be a potent stimulus to renin release in some of the patients.     

Fast liquid chromatographic determination of urinary trans,trans-muconic acid

trans,trans-Muconic acid (1,3-butadiene-1,4-dicarboxylic acid, MA), a minor urinary metabolite of benzene exposure, was determined, after clean-up by solid-phase anion-exchange chromatography, by reversed-phase HPLC on a C₁₈ column (5 × 0.46 cm I.D., 3 μm particle size), using formic acid-tetrahydrofuran-water (14:17:969) as mobile phase and UV detection at 263 nm. The recovery of MA from spiked urine was > 95% in the 50–500 μg/l range; the quantification limit was 6 μg/l; day-to-day precision, at 300 μg/l, C.V. = 9.2%; the run time was less than 10 min. Urinary MA excretion was measured in two spot urine samples of 131 benzene environmentally exposed subjects: midday values obtained in non-smokers (mean±S.D.=77±54 μg/l, N = 82) were statistically different from those of smoerks (169±85 μg/l, N = 30) (P<0.0001); each group showed a statistically significant increase between MA excretion in midday over morning samples. Moreover, in subjects grouped according to tobacco-smoke exposure level, median values of MA were positively associated with and increased with daily smoking habits.     

Prostaglandin biosynthesis in rabbit kidney medulla: Inhibition vs. by aspirin, indomethacin and meclofenamic acid

The non-steroidal anti-inflammatory drugs aspirin, indomethacin and meclofenamic acid were compared for their potency and duration of inhibition of prostaglandin biosynthesis in rabbit kidney medulla. Indomethacin and meclofenamic acid showed equal potency of inhibition (IC₅₀ 0.88 μM and 0.85 μM respectively) while aspirin was a much weaker inhibitor (IC₅₀ 120 μM). , indomethacin was the most powerful inhibitor (ID₅₀ 0.034 mg/kg) followed by meclofenamic acid (0.45 mg/kg) and aspirin (2.35 mg/kg).Studies on the duration of inhibition by these compounds showed the effect of indomethacin and meclofenamic acid to be completely reversed within 4–6 hours. In contrast, return of kidney prostaglandin biosynthetic activity following aspirin inhibition is very slow and significant inhibition is still present 48 hours after a single aspirin injection. The inhibitory effect of aspirin could be blocked by pretreatment with indomethacin, indicating that both drugs interact with related sites on the cyclo-oxygenase enzyme. The irreversible inhibition of the cyclo-oxygenase by aspirin as demonstrated in studies of other investigators suggests that the return of kidney prostaglandin synthetase activity after aspirin inhibition represents synthesis of new cyclo-oxygenase protein.     

Double isotope derivative dilution method for the determination of prostaglandin F and E type metabolites in urine

This method was developed for the quantitative determination of the main urinary metabolite (MUM) of prostaglandin (PG) F and E type in man or experimental animal. This method was based on the extraction of PG-MUM after addition of ³H-PG-MUM, the esterification with ¹⁴C-acetic anhydride and the separation and purification by column chromatography. Excretion values of adult men were PGF-MUM 1.46–15.01 μg/8 hr (n=11), PGE-MUM 0.82–15.42 μg/8 hr; and with women, PGF-MUM 0.41–7.75 μg/8 hr (n=11), PGE-MUM 0.60–11.39 μg/8 hr.     

Modulation of prostaglandin of the renal vascular action of arginne vasopressin

To determine whether the renal vascular effect of arginine vasopressin (AVP) is modulated by renal prostaglandin E₂ (PGE₂) were determined during the infusion of AVP in dogs during control conditions and after the administration of the inhibitor of prostaglandin synthesis, indomethacin. During control conditions, intrarenal administration for 10 min of a dose of AVP calculated to increase arterial renal plasma AVP concentration by 75 pg/ml produced a slight renal vasodilation (p<0.01) and an increase in renal venous plasma concentration of PGE₂. Renal venous PGE₂ concentration during control and AVP infusion averaged 33 ± 7 and 52 ± 12 pg/ml (p<0.05), respectively. After administration of indomethacin, the same dose of AVP induced renal vasoconstriction (p<0.05) and failed to enhance renal venous PGE₂ concentration (9 ± 1 to 8 ± 1 pg/ml). Intrarenal administration of 20 ng/kg. min of AVP for 10 min induced a marked renal vasoconstriction (p<0.01) and increased renal venous plasma PGE₂. Renal venous PGE₂ during control and AVP infusion averaged 31 ± 10 and 121 ± 31 pg/ml (p<0.01), respectively. Administration of the same dose of AVP following indomethacin produced a significantly greater and longer lasting renal vasoconstriction (p<0.01) and failed to increase renal venous plasma PGE₂ (10 ± 1 to 9 ± 1 pg/ml). These results indicate that a concentration of AVP comparable to that observed in several pathophysiological conditions induces a slight renal vasodilation which is mediated by renal prostaglandins. The results also indicate that higher doses of AVP induce renal vasoconstriction and that prostaglandin synthesis induced by AVP attenautes the renal vasoconstriction produced by this peptide.     

The development of tone in the smooth muscle of guinea-pig isolated tracheal preparations may be influenced by prostanoids released from the adjacent airway cartilage

Guinea-pig tracheal strip preparations containing cartilage, placed under an applied load , develop tone spontaneously. The finding that spontaneous tone is reduced by indomethacin suggests that one or more prostanoids are involved in the development of spontaneous tone in this species. In this study we examined the effects of removing the cartilage component of the preparations on changes in tone induced by indomethacin and isoproterenol. In contrast to preparations containing cartilage, tissues devoid of cartilage, did not develop tone after the application of an initial 1 g resting load. Indomethacin (1 μM) reduced resting tone by 0.62 ± 0.14 g in cartilage-containing tissues but, in contrast, reduced tone by only 0.03 ± 0.01 g in tissues devoid of cartilage. Furthermore, relaxation responses (0.38 ± 0.05 g) to isoproterenol (1 μM) could be produced in cartilage-containing preparations but not in cartilage-free preparations. Radioimmunoassays indicated that the release of PGE₂, PGF_2α and 6-keto PGF_1α, the end-product of PGI₂ breakdown, was diminished in preparations lacking cartilage. Thus, in guinea-pig airway preparations cartilage is apparently a source of sufficient prostanoids to induce spontaneous tone     

Blood pressure and heart rate effects of prostaglandin E2 and F2α produced by intracerebroventricular injections in cats

Blood pressure and heart rate effects of prostaglandin E₂ and F_2α were examines after administrating each agent into the left lateral brain ventricle of chloralose-anesthethized cats. Administration of prostaglandin E₂ (1 μg) resulted in significant, prolonged increases in arterial pressure (25.7 ± 6.7 mm Hg) and heart rate (19.4 ± 7.7 beats/min). These responses were mimicked when the same dose of prostagland E₂ was administered into the restricted to the lateral and third ventricles via cannulation of the cerebral aqueduct, whereas no significant cardiovascular occured with administration into the fourth ventricle. Intravenous injection of prostaglandin E₂ resulted in a transient decrease in blood pressure but no change in heart rate. Administration of prostaglandin F_2α (1 and 3 μg) into the CNS produced no significant cardiovascular responses. The same was true when prostaglandin F_2α was administered by the intravenous route. These results indicate that pronounced cardiovascular effects can be produced by administering prostaglandin E₂ but not F_2α into the CNSm and that the central site of action of prostaglandin E₂ is in the forebrain.     

Biological monitoring of hexamethylene diisocyanate by determination of 1,6-hexamethylene diamine as the trifluoroethyl chloroformate derivative using capillary gas chromatography with thermoionic and selective-ion monitoring

A GC method using a novel derivatization reagent, 2′,2′,2-trifluoroethyl chloroformate (TFECF), for the derivatization of primary and secondary aliphatic amines with the formation of carbamate esters is presented. The method is based on a derivatization procedure in a two-phase system, where the carbamate ester is formed. The method is applied to the determination of 1,6-hexamethylene diamine (HDA) in aqueous solutions and human urine, using capillary GC. Detection was performed using thermionic specific detection (TSD) and mass spectrometry (MS)—selective-ion monitoring (SIM) using electron-impact (EI) and chemical ionization (CI) with ammonia monitoring both positive (CI)⁺ and negative ions (CI)⁻. Quantitative measurements were made in the chemical ionization mode monitoring both positive and negative ions. Tetra-deuterium-labelled HDA (TDHDA; H₂NC²H₂(CH₂)₄C²H₂NH₂) was used as the internal standard for the GC—MS analysis. In CI⁺ the m/z 386 and the m/z 390 ions corresponding to the [M + 18]⁺ ions (M = molecular ion) of HDA—TFECF and TDHDA—TFECF were measured; in CI⁻ the m/z 267 and the m/z 271 ions corresponding to the [M — 101]⁻ ions. The overall recovery was found to be 97 ± 5% for a HDA concentration of 1000 μg/l in urine. The minimal detectable concentration in urine was found to be less than 20 μg/l using GC—TSD and 0.5 μg/l using GC—SIM. The overall precision for the work-up procedure and GC analysis was ca. 3% (n = 5) for 1000 μg/l HDA-spiked urine, and ca. 4% (n = 5) for 100 μg/l. The precision using GC—SIM for urine samples spiked to a concentration of 5 μg/l was found to be 6.3% (n = 10).     

Inhibition of prostaglandin synthesis in man

7α-Hydroxy-5,11-diketotetranor-prostane-1,16-dioic acid, the major urinary metabolite of prostaglandins E₁ and E₂ in man, was determined in human urine by a method based on the use of the bis (O-²H₃-methyloxime) derivative of dimethyl 7α-hydroxy-5,11-diketotetranor-prostane-1,16-dioate as internal standard and determination of the ratio between unlabeled and deuterium-labeled molecules by multiple-ion analysis. Male subjects excreted larger amounts of the metabolite (6.5–46.7 μg/24 hours, n=10) than did female subjects (2.5–5.3 μg/24 hours, n=10). The excretion rate was strongly suppressed following oral administration of therapeutic doses of indomethacin, aspirin and sodium salicylate.