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PubMed2006

Crystal structure of anti-configuration of indomethacin and leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase complex reveals the structural basis of broad spectrum indomethacin efficacy.

The crystal structure of the ternary complex of leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin (15-oxo-PG) 13-reductase (LTB4 12HD/PGR), an essential enzyme for eicosanoid inactivation pathways, with indomethacin and NADP+ has been solved. An indomethacin molecule bound in the anti-configuration at one of the two active site clefts of the homo-dimer interface in the LTB4 12HD/PGR and was confirmed by a binding calorimetry. The chlorobenzene ring is buried in the hydrophobic pore used as a binding site by the omega-chain of 15-oxo-PGE2. The carboxyl group interacts with the guanidino group of Arg56 and the phenolic hydroxyl group of Tyr262. Indomethacin shows a broad spectrum of efficacy against lipid-mediator related proteins including cyclooxygenase-2, phospholipase A2, PGF synthase and PGE synthase-2 but in the syn-configuration as well as LTB4 12HD/PGR in the anti-configuration. Indomethacin does not necessarily mimic the binding mode of the lipid-mediator substrates in the active sites of these complex structures. Thus, the broad spectrum of indomethacin efficacy can be attributed to its ability to adopt a range of different stable conformations. This allows the indomethacin to adapt to the distinct binding site features of each protein whilst maintaining favorable interactions between the carboxyl group and a counter charged functional group.

15-Oxoprostaglandin 13-Reductase↗
PubMed1989

Kinetics of hydrolysis of indomethacin and indomethacin ester prodrugs in aqueous solution.

The kinetics of hydrolysis of indomethacin and a glycolamide ester of the drug was studied to assess the possibility of designing a water-soluble and solution-stable prodrug of indomethacin suitable for parenteral or ocular administration. The pH-rate profiles for these compounds were obtained at 60 degrees C and were accounted for by specific acid and base catalytic reactions as well as by a water-catalyzed hydrolysis. From temperature-accelerated studies, pH-rate profiles at 25 degrees C were predicted. Indomethacin and its ester showed maximal stability at pH 4.9 and 4.7, respectively, the shelf lives at these pH values and 25 degrees C being 2.0 years for indomethacin but only 43 days for the ester. The ester degrades both at its ester group and at the indole amide group of the indomethacin moiety, and shows a very pronounced water-catalyzed hydrolysis which accounts for the limited stability. It is concluded that the design of an indomethacin ester prodrug with a stability allowing formulation of a ready-to-use aqueous solution may be difficult.

Chromatography, High Pressure Liquid↗
PubMed1977

The effect of indomethacin on kidney function: indomethacin and furosemide antagonism.

The effect of furosemide and indomethacin on renal function was investigated in anesthetized dogs. 1. On infusing 0.05 mg/kg/min furosemide directly into the left renal artery, about 18% of the filtered water and 19% of the filtered sodium was excreted in both non-hydrated and hydrated dogs. 2. Under the effect of 0.1 mg/kg/min indomethacin administered intravenously renal blood flow decreased markedly, glomerular filtration rate remained unchanged, the filtration fraction increased. 3. Indomethacin induced a decrease in water and sodium rejection and water and sodium excretion in both the hydrated and non-hydrated animals. 4. Indomethacin inhibited the diuretic effect of furosemide in the non-hydrated animals. This effect was much weaker in the hydrated group. These data suggest that in the anesthetized dog, endogenous prostaglandins may serve to maintain renal blood flow but not glomerular filtration rate. It is concluded that the indomethacin-induced inhibition of the furosemide effect is the consequence of hemodynamic changes occurring in the kidney. The data do not support the direct physiological role of prostaglandins in regulating tubular function.

Animals↗
PubMed2003

Prophylactic indomethacin reduces grades III and IV intraventricular hemorrhages when compared to early indomethacin treatment of a patent ductus arteriosus.

OBJECTIVE: To determine the relative risk of severe intraventricular hemorrhage (IVH) between two very early indomethacin treatment strategies. STUDY DESIGN: Retrospective chart review of infants <29 weeks gestation and <1350 g who received either indomethacin prophylaxis or very early echocardiography with indomethacin treatment only if the ductus arteriosus was patent. RESULTS: A total of one hundred and two infants received prophylactic indomethacin (pINDO). Echochardiography was performed on 158 infants, of whom 117 received indomethacin. Infants receiving pINDO had lower gestational age, but similar birth weight, gender, race, antenatal steroid exposure, delivery mode, Apgar scores, and need for resuscitation as infants evaluated by echocardiography. Grades III to IV IVH was observed less frequently in infants who received pINDO (OR 0.27, 95% CI 0.10 to 0.77, p=0.014). Frequency of side effects and recurrent patent ductus arteriosus did not differ between treatment groups. CONCLUSION: pINDO reduces severe IVH when compared to an early echocardiography strategy.

Cardiovascular Agents↗
PubMed2005

Enhancement of transformed foci and induction of prostaglandins in Balb/c 3T3 cells by palytoxin: in vitro model reproduces carcinogenic responses in animal models regarding the inhibitory effect of indomethacin and reversal of indomethacin's effect by exogenous prostaglandins.

Cell transforming activity of palytoxin, a non-TPA type tumor-promoter, was investigated with the two-stage transformation assay using Balb/c 3T3 cells. Palytoxin showed potent promoting activity; treatment at 1.9 pM or more increased the number of transformed foci after initiation by 3-methylcholanthrene (MCA). Determination of prostaglandin (PG) E2 and PGF(2alpha) concentrations in the culture medium revealed that palytoxin (1.9-3.7 pM for 24 h) stimulated the production of PG in Balb/c 3T3 cells (the concentration reached 3-4 microM), and treatment with PGE2 or PGF(2alpha) itself increased the number of transformed foci of Balb/c 3T3 cells after initiation by MCA. Neither palytoxin nor PGs showed initiating activity. Indomethacin suppressed the promoting activity of palytoxin, but not that of PGE2 and PGF(2alpha). Interestingly, concomitant treatment with PGE2 or PGF(2alpha) in addition to indomethacin markedly reversed the suppressive effect of indomethacin. These findings indicated that the in vitro transformation model could reproduce experiments that have been performed in animal models regarding the inhibitory effect of indomethacin on carcinogenic responses and reversal of indomethacin's effect by exogenous prostaglandin and, therefore, may provide insight into molecular modes of action of palytoxin. In the present study, palytoxin also induced prostaglandin synthesis, and therefore, the Balb/c 3T3 cell model should provide insight into the molecular mechanism by which palytoxin regulates prostaglandin biosynthesis.

Acrylamides↗
PubMed1983

Indomethacin treatment in small versus large premature infants with ductus arteriosus. Comparison of plasma indomethacin concentration and clinical response.

An analysis of clinical response and plasma indomethacin concentration was performed on 10 small (less than or equal to 1000 g) and 12 large (greater than 1000 g) premature infants who had symptomatic ductus arteriosus and required intravenous indomethacin therapy (0.3 mg/kg per day). The postnatal age, daily fluid intake, and cardiopulmonary status of the two groups at time of study were comparable, The small premature infants had a significantly lower peak plasma indomethacin concentration and lower concentration in the first four hours after infusion, and lower plasma concentration X time integral than that of the larger premature infants. There was a significant difference between the groups in proportion of response (2/10 vs 9/12) after one dose of indomethacin; this difference was not seen after two to three doses. The results of the study suggest that small premature infants do respond to indomethacin treatment, but compared to the larger infants may require repeated doses.

Birth Weight↗
PubMed1984

Gastric microbleeding measurements during one day treatment with indomethacin and indomethacin plus sodium salicylate (1 : 10) in patients.

A double-blind, prospective, randomized clinical study was carried out. Gastric microbleeding was provoked in informed patients without gastrointestinal disorders by the administration of indomethacin (4 X 25 mg, orally), sodium salicylate (4 X 250 mg, orally) or indomethacin (25 mg) plus sodium salicylate (250 mg) (Pelsonin, 4 X 1 capsules). The rate of gastric bleeding was estimated on the basis of haemoglobin losses into the gastric juice according to a rapid and sensitive chemical method (Fisher and Hunt, 1976). The observations were done before and after the day of treatment. The basic gastric bleeding was practically the same in the three groups (indomethacin, 0.91 +/- 0.12 ml/day: sodium salicylate, 0.72 +/- 0.20 ml/day: Pelsonin, 0.99 +/- +/- 0.18 ml/day: p less than 0.05). Contrary to this, the increases of gastric bleeding were found to be considerably different after a one-day application of these drugs (indomethacin, 7.3 +/- 1.2 ml/day: sodium salicylate, 1.92 +/- 0.45 ml/day, Pelsonin, 2.1 +/- 0.8 ml/day). It has been concluded that sodium salicylate can reduce the indomethacin-induced gastric microbleeding in patients.

Adult↗
PubMedDate not supplied

A double-blind randomized placebo controlled gastroscopic study to compare the effects of indomethacin capsules and indomethacin suppositories on the gastric mucosa of human volunteers.

Forty-five normal volunteers were divided into 3 equal groups, each receiving indomethacin or placebo once daily in he evening as a capsule or suppository for 10 days. The dose of indomethacin was 50 mg for the first 5 days and 100 mg for the second 5 days. Endoscopic evaluation of the gastric mucosa was carried out on days 1, 6 and 11. It was found that indomethacin capsules caused significantly more gastric irritation than indomethacin suppositories (p less than .01) or placebo (p less than .0001). No significant difference was found in the incidence of gastric injury observed in the indomethacin suppository and placebo groups.

Administration, Oral↗
PubMed1982

A double-blind trial comparing indomethacin sustained release capsules (Indocid-R) with indomethacin capsules in patients with rheumatoid arthritis.

A double-blind, controlled and completely randomized trial was conducted in four European rheumatology clinics. Eighty-six patients with a diagnosis of rheumatoid arthritis and prior treatment of at least six months' duration with indomethacin 150 mg/day were studied. Comparisons of the clinical efficacy, tolerability and safety of a new, oral sustained-release formulation of indomethacin were made with a conventional formulation of indomethacin. In all clinical indices of response, the indomethacin sustained-release 75 mg capsule b.i.d. was found to provide relief of symptoms similar to the conventional 50 mg capsule t.i.d. The incidence of overall adverse clinical and laboratory effects was comparable for the two treatments.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1981

Clinical effects of indomethacin and additive clinical effect of indomethacin during salicylate maintenance therapy.

Studies on the therapeutic effect of nonsteroidal anti-inflammatory agents in relation to doses or plasma concentrations have been relatively rare. We have investigated the clinical effects of indomethacin in daily doses of 45, 75 and 105 mg compared with placebo. The treatments were given double blind in two-week periods to eight rheumatic patients. There was a statistically significant therapeutic effect on parameters related to pain but no effect was detected on the activity of the disease by technetium scintigraphy. There was no clear association between dose or plasma concentration of indomethacin and therapeutic response in the actual patients with the dose range used. In a subsequent study ASA was given double blind in daily doses of 2 and 4.5 g in two three-week periods to twelve rheumatic patients. Placebo and indomethacin were given as suppositories at night and the clinical effect was evaluated by articular index and subjects rating of morning stiffness and pain. Prostaglandin release from platelets was assessed by a RIA method. It was found that both doses of ASA suppressed the PGF2alpha release totally. Indomethacin had a significant additive effect during 2 g ASA therapy as estimated by articular index and subjective ratings of pain and morning stiffness. On the 4.5 g ASA dose there was a significant improvement only for articular index. Thus the release of PGF2alpha cannot be used as a measure of antirheumatic effect and the clinical practice to combine these drugs seems justified. As the dose of ASA was increased from 2 to 4.5 g daily the total salicylate concentration increased up to 5 times. The unbound and pharmacologically active concentration increased up to 24 times. This disproportionality reflects the combined effect of capacity limited metabolism and capacity limited protein binding of salicylate.

Arthritis, Rheumatoid↗
PubMed1979

A comparative study with indomethacin and combined indomethacin sodium-salicylate in rheumatoid arthritis.

A double-blind cross-over clinical trial was performed to compare clinical effectiveness of indomethacin (3 x 25 mg/day) alone to that of a combination of indomethacin + sodium-salycylate (3 x 25 mg/day and 3 x 250 mg/day, respectively) in rheumatoid arthritis. It was established that enteral blood loss was significantly reduced by combined treatment as determined by Cr51 labelled erythrocytes in comparison to that after treatment with indomethacin alone. Therapeutic effect was maintained in both groups, no significant disparities were observed. Occurrence of subjective complaints was less frequent in the combined treatment group. It was concluded that the combined preparation consisting of indomethacin and sodium-salicylate has a favourable effect in rheumatoid arthritis.

Adult↗
PubMed1977

[Pharmacokinetics of indomethacin and indomethacin metabolites administered continuously to patients with healthy or damaged kidneys].

After oral administration of 75 mg Indomethacin dlimination half-life of the unchanged drug is not altered in patients with severely impaired renal function. In patients with renal insufficiency half-life of Indomethacin plus metabolites is twice that of the normal value. Repeated daily administration of 75 mg for 8 days does not influence Indomethacin kinetics. In the control group and in patients with moderate by impaired renal function Indomethacin half-life does not change during chronic administration.

Half-Life↗
PubMed1997

Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three-year-old woman treated with indomethacin.

In patients with acute liver failure, cerebral herniation is a common cause of death. The present study reports the effect of indomethacin on four occasions of intracranial hypertension, in a 23-year old previously healthy woman with severe acetaminophen poisoning. During each episode of intracranial hypertension, the patient was treated with 25 mg of indomethacin, and each time the intracranial pressure normalized. We recommend further controlled studies to determine the exact effect of indomethacin on cerebral blood flow and metabolism before it is recommended for treatment of intracranial hypertension in patients with acute liver failure.

Acute Disease↗
PubMed1987

Bioavailability of indomethacin from a modified release system containing indomethacin as the lysine salt.

The bioavailability of a new controlled release formulation of indomethacin lysine salt in tablets was tested in 6 healthy humans against a conventional indomethacin lysinate formulation in capsules. Both contained 100 mg of the drug, i.e. 70 mg indomethacin. Peak plasma levels were lower and more lasting and the AUC was higher with the new controlled release formulation. The latter on average produced active plasma levels for 12 h, and so it can be recommended for twice daily administration.

Biological Availability↗
PubMed1985

Pharmacokinetic overview of indomethacin and sustained-release indomethacin.

Indomethacin has a moderately short half-life, usually requiring dosing twice a day or three times a day. A more convenient once or twice daily regimen is made possible with a sustained-release formulation. Following multiple-dose administration of either sustained-release indomethacin (Indocin SR) or conventional indomethacin, drug accumulation is low. Clinical studies indicate comparable safety and efficacy profiles between the two preparations. Pharmacokinetic information on both dosage forms is reviewed.

Absorption↗
PubMed2005

Understanding agglomeration of indomethacin during the dissolution of micronised indomethacin mixtures through dissolution and de-agglomeration modeling approaches.

The purpose of this research was to correlate the state of agglomeration determined by the modeling of dissolution and de-agglomeration profiles, using mixtures of micronised indomethacin designed to have different dissolution rates and extents of particle agglomeration in dissolution media. Dissolution profiles were determined using the USP paddle method. De-agglomeration profiles were obtained from laser diffraction particle sizing of mixtures of indomethacin in dissolution media under non-sink conditions. Data were modeled and key parameters estimated using a non-linear least squares estimation algorithm. The key parameters of initial apparent volume concentrations as dispersed and agglomerated particles, and dissolution rate constants (for dissolution modeling), and the apparent volume concentrations of dispersible and non-dispersible agglomerates and the de-agglomeration rate constant (for de-agglomeration modeling) were related to indomethacin and sodium lauryl sulphate concentrations in the lactose-povidone mixtures. Micronised sodium lauryl sulphate added to the mixture was more effective in de-agglomeration than equivalent concentrations in the dissolution media. An excellent correlation existed between the total initial apparent volume concentration of agglomerates determined by dissolution and de-agglomeration (P=0.98). The use of key parameters estimated from the modeling of dissolution and de-agglomeration profiles provides a useful tool in dosage form development of formulations of poorly water soluble drugs.

Chemistry, Pharmaceutical↗
PubMed1991

Indomethacin ion-selective electrode based on a bis(triphenylphosphoranylidene)ammonium-indomethacin complex.

The properties of an ion-selective electrode for indomethacin based on the bis(triphenylphosphoranylidene)ammonium-indomethacin ion-pair complex in a poly(vinyl chloride) membrane are described. The detection limit found for indomethacin at pH 7.0 was 2 x 10(-5) mol l-1 (6.4 micrograms ml-1) and the linear range was determined to be between 5 x 10(-5) and greater than or equal to 10(-3) mol l-1. The selectivity coefficients observed for organic anions of different lipophilicity were 10(-1.1) for naproxenate, 10(-0.75) for salicylate and less than 10(-4) for tartrate. Cationic organic and inorganic ions showed negligible interference with selectivity coefficients of less than 10(-4). A strong electrode response was observed for the inorganic anions IO4-, ClO4- and SCN- with selectivity coefficients of up to 10(+0.9). Very low detection limits, e.g., 6 x 10(-7) mol l-1 (60 ng ml-1) for ClO4- were found. The selectivity for inorganic anions was close to the Hofmeister series.

Electrodes↗
PubMed1980

Effects of indomethacin on the metabolism of glycerol by rat-kidney tubules: an alternative explanation for the enhancement of glycerol-induced acute renal failure by indomethacin.

1. The metabolism of glycerol by isolated rat-kidney tubules was investigated. 2. Indomethacin, at a concentration of 0.1 mmol/l, markedly inhibited the utilization of glycerol and its conversion into glucose and CO2. 3. The glycerol 3-phosphate production rose significantly when indomethacin was present, indicating a fall in the rate at which glycerol 3-phosphate was oxidized. 4. The results are discussed in relation to the observation that indomethacin increases the severity of glycerol-induced acute renal failure.

Acute Kidney Injury↗