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PubMed2000

Syntheses and characterization of anti-inflammatory dinuclear and mononuclear zinc indomethacin complexes. Crystal structures of [Zn2(indomethacin)4(L)2] (L = N,N-dimethylacetamide, pyridine, 1-methyl-2-pyrrolidinone) and [Zn(indomethacin)2(L1)2] (L1 = ethanol, methanol).

The syntheses and spectral and structural characterizations of Zn(II) indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid = IndoH] complexes, as different solvent adducts, have been studied. The complexes are unusual in that both monomeric and dimeric complexes are formed and that this is the first example of the same carboxylato ligand binding via both carboxylate oxygen atoms in monomeric and dimeric Zn(II) complexes. The crystal structures of Zn-Indo complexes with N,N-dimethylacetamide (DMA), pyridine (Py), 1-methyl-2-pyrrolidinone (NMP), EtOH, and MeOH as solvent ligands, [Zn2(Indo)4(DMA)2].2DMA, 1, [Zn2(Indo)4(Py)2].2H2O, 2b, [Zn2(Indo)4(NMP)2], 3, cis-[Zn(Indo)2(EtOH)2], 4, and cis-[Zn(Indo)2(MeOH)2], 5, were determined. Complexes 1, 2b, and 3 crystallize in the triclinic space group P1 (No. 2): a = 13.628(2) A, b = 17.462(2) A, c = 11.078(1) A, alpha = 99.49(1) degrees, beta = 108.13(1) degrees, gamma = 110.10(1) degrees for 1; a = 13.347(3) A, b = 16.499(5) A, c = 10.857(1) A, alpha = 99.48(2) degrees, beta = 108.25(2) degrees, gamma = 106.24(2) degrees for 2; a = 14.143(3) A, b = 14.521(2) A, c = 11.558(2) A, alpha = 109.07(1) degrees, beta = 90.80(2) degrees, gamma = 116.40(1) degrees for 3. The three complexes exhibit dinuclear paddle-wheel structures with a Zn...Zn distance of 2.9686(6) A, Zn-ORCOO distances of 2.035(2)-2.060(2) A, and a Zn-ODMA distance of 1.989(2) A in 1, a Zn...Zn distance of 2.969(1) A, Zn-ORCOO distances of 2.020(3)-2.049(3) A, and a Zn-NPy distance of 2.036(3) A in 2, and a Zn...Zn distance of 2.934(1) A, Zn-ORCOO distances of 2.009(3)-2.051(3) A, and a Zn-ONMP distance of 1.986(3) A in 3. In these cases, the zinc ions are offset along the z direction such that the L-Zn...Zn-L moiety is nonlinear, unlike the Cu analogues. Each Zn has a square-pyramidal geometry bridged by four carboxylato ligands in the basal plane with the solvent ligands containing an O- or N-donor atom at the apex. Complexes 4 and 5 are isostructural, with space group C2/c (No. 15). For 4, a = 30.080(2) A, b = 5.3638(6) A, c = 24.739(2) A, beta = 90.342(7) degrees, and for 5, a = 29.419(2) A, b = 5.320(2) A, c = 24.461(2) A, beta = 90.840(4) degrees. The Zn resides on a 2-fold axis and the complexes have a distorted cis octahedral structure with Zn-ORCOO bond lengths of 2.183(3) and 2.169(3) A, a Zn-OEtOH bond length of 2.015(3) A in 4, Zn-ORCOO bond lengths of 2.195(2) and 2.151(2) A, and a Zn-OMeOH bond length of 2.022(3) A in 5.

Anti-Inflammatory Agents↗
PubMed2000

Intravenous indomethacin for preventing mortality and morbidity in very low birth weight infants.

BACKGROUND: This section is under preparation and will be included in the next issue. OBJECTIVES: Indomethacin is used to treat symptomatic patent ductus arteriosus and may prevent or limit intraventricular haemorrhage in the neonatal period. This review examines the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with these conditions in infants weighing less than 1750 grams at birth. SEARCH STRATEGY: A literature search from January 1980 to October 1994 was made in three computerised data bases: Medline; Embase; and the Oxford Database of Perinatal Trials. The search was updated in February 1997. SELECTION CRITERIA: Strict selection criteria were applied to clinical trials: the population had to be newborn infants of birth weight < 1751 grams; the intervention had to be prophylactic intravenous indomethacin; the trial had to be randomised and controlled; and at least one of several prespecified outcomes had to be reported in the results. DATA COLLECTION AND ANALYSIS: The methodological quality of each study was assessed using explicit criteria. Data on relevant outcome measures were extracted on two separate occasions and, where appropriate, the results of individual trials were combined using meta-analysis techniques to provide a pooled estimate of effect. MAIN RESULTS: There is a trend towards reduced neonatal mortality in infants receiving prophylactic indomethacin, pooled relative risk (RR) = 0. 85 [95% CI 0.66 to 1.09]. The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled RR = 0.35 [0.26 to 0.47] but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin significantly reduces the incidence of Grade 3 and 4 intraventricular haemorrhage in treated infants, pooled RR = 0.60 [0.43 to 0.83]. There is no evidence to suggest prophylactic indomethacin is associated with any long term adverse effect although there is a trend in treated infants towards an increased incidence of necrotizing enterocolitis, and some evidence that treatment may transiently impair renal function. There is no evidence that haemostasis is disturbed. REVIEWER'S CONCLUSIONS: Prophylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic patent ductus arteriosus and severe intraventricular haemorrhage. There is no evidence at present of long-term harm. Further trials are needed to assess more precisely the effects, both beneficial and harmful, on short and long-term outcomes.

Cardiovascular Agents↗
PubMed2000

Furosemide for symptomatic patent ductus arteriosus in indomethacin-treated infants.

BACKGROUND: Inhibition of prostaglandin synthesis mediates closure of the ductus arteriosus and renal side effects after indomethacin administration. Because furosemide increases prostaglandin production, it could potentially help prevent indomethacin-related toxicity but also decrease ductal response to indomethacin. OBJECTIVES: The primary objectives of this review were to assess (1) whether furosemide affects the incidence of failure of ductal closure after indomethacin and that of indomethacin-related toxicity and (2) the effect of furosemide on mid-term and long-term outcome. The secondary objective was to determine whether the effect of furosemide on renal function and water balance depends on prior extracellular volume (assessed by blood urea nitrogen [BUN]/creatinine ratio). SEARCH STRATEGY: We searched electronic databases (Medline, Embase and Cochrane) and selected abstract books, without language restriction. SELECTION CRITERIA: We selected studies with (1) random allocation to either indomethacin alone or indomethacin and furosemide and (2) analysis of either short-term risk-benefit ratio of furosemide, mid- or long-term outcome, or the relationship between extracellular volume at study entry and changes in renal function. DATA COLLECTION AND ANALYSIS: We assessed studies for possible bias and for quality of assessment of ductal patency. We assessed categorical variables using relative risk and absolute risk reduction. We assessed the effects of furosemide on renal function and fluid balance by comparing changes from baseline in the treatment group with those in controls. Subsets were determined a priori based on BUN/creatinine ratio at study entry. MAIN RESULTS: All 3 studies fulfilling the entry criteria had limitations, including possible or definite bias. There was substantial heterogeneity among studies. Furosemide administration did not significantly increase the risk of failure of ductal closure; however, sample size was insufficient to rule out even a 31% increase. In the subset with initial BUN/creatinine ratio > 20 mg/mg, 2 of 18 patients receiving furosemide could not complete a 3-dose course of indomethacin because of toxicity. Minimal or no information was available about any of the other main outcome variables. Furosemide increased urine output regardless of the initial BUN/creatinine ratio, leading to a 5% weight loss during a 3-dose course, an undesired effect in patients with initial BUN/creatinine ratio > 20 mg/mg. Furosemide increased creatinine clearance only in patients with initial BUN/creatinine ratio <20 mg/mg. REVIEWER'S CONCLUSIONS: There is not enough evidence to support the administration of furosemide to premature infants treated with indomethacin for symptomatic patent ductus arteriosus. Furosemide appears to be contraindicated in the presence of dehydration in those infants.

Cyclooxygenase Inhibitors↗
PubMedDate not supplied

[Indomethacin kinetics and urinary excretion of prostaglandin E2 following oral administration of various dosage forms of indomethacin].

In a controlled crossover study healthy volunteers received a single oral dose of 75 mg indomethacin, 75 mg sustained-release indomethacin, or the new therapeutic system indomethacin Gits 7/85. Dependence on the time of administration was investigated by comparing the plasma level curves obtained following morning and evening administration of indomethacin and indomethacin Gits. Blood samples were taken at defined intervals following administration for determination of indomethacin plasma levels. To determine urinary excretion of prostaglandin (PG)E2, urine was collected during four consecutive 6 h-clearance periods after administration of the indomethacin preparations. The plasma level curve following administration of indomethacin Gits 7/85 did not exhibit clearly distinct initial peaks and, in contrast to the other drug preparations, remained nearly constant over 10-12 h. Indomethacin induced a significant suppression of urinary PGE2 excretion over a period of 12 h, whereas both sustained release indomethacin and indomethacin Gits 7/85 decreased urinary PGE2 excretion for 18 h. Neither the plasma concentration curve of indomethacin nor the inhibitory effect on urinary PGE2 excretion was dependent on the time of administration. Initial central nervous side effects, such as dizziness, were reported by all volunteers after taking indomethacin and by half of the volunteers following sustained release indomethacin, whereas no adverse effects were observed after administration of indomethacin Gits 7/85. The present study demonstrates that indomethacin Gits 7/85 produces no initial peaks of plasma levels but rather a sustained concentration plateau. The excellent tolerability of indomethacin Gits 7/85 is probably due to the lack of peak plasma concentrations.

Administration, Oral↗
PubMed1975

Interaction of indomethacin and acetylsalicylic acid as shown by the serum concentrations of indomethacin and salicylate.

A clinical-pharmacological study was performed to determine the effect of acetylsalicylic acid upon the serum concentration of indomethacin. 14 rheumatic patients were given indomethacin orally (25 mg X 4 for 4 days) and concurrently acetylsalicylic acid 3.7 g orally (0.9 g X 3 and 1.0 g X 1 daily), and 21 rheumatic patients were given indomethacin rectally in the morning (100 mg X 1) and concurrently acetylsalicylic acid 3.7 g orally (0.9 g X 3 and 1.0 g X 1 daily). On comparison with treatment with oral or rectal indomethacin alone, it was found that peak serum concentrations of indomethacin were significantly reduced (1% level), the times of the peaks were not shifted, and the areas beneath the serum concentration curves of indomethacin were smaller, but significantly so only if compared with rectal administration. In 12 rheumatic patients given indomethacin by rectum in the evening (100 mg X 1) and concurrently acetylsalicylic acid 3.7 g (0.9 g X 3 and 1.0 g X 1 daily), the serum level of indomethacin on the following morning (after 11 h) did not differ from that found after rectal treatment. A statistically but not biologically significant difference was observed between the mean serum half-lives of indomethacin given orally and rectally. For unknown reasons, concurrent doses of acetylsalicylic acid and indomethacin made the mean serum half-life of indomethacin longer than after its oral administration, but shorter than when the same dose of indomethacin was given rectally. There was no difference between serum levels of salicylate after oral administration of acetylsalicylic acid alone or after a concurrent oral or rectal dose of indomethacin. The results have been related to those reported previously, with respect to the interaction between indomethacin and acetylsalicylic acid, the serum levels of indomethacin after oral and rectal dosing, and the serum half-life of indomethacin based upon a one- or two-compartment model. The clinical relevance of the study is discussed.

Administration, Oral↗
PubMed1988

Effect in man of aspirin, standard indomethacin, and sustained release indomethacin preparations on gastric bleeding.

1. We have compared acute gastric bleeding caused by a new slow release preparation of indomethacin (indomethacin Continus) with that caused by aspirin and other indomethacin preparations. 2. In a randomized crossover study, blood loss into timed gastric aspirates was determined in 20 healthy volunteers after receiving, over 96 h, either placebo, aspirin (600 mg four times daily; 17 doses) indomethacin BP (50 mg three times daily; 13 doses), Indocid-R (75 mg twice daily; 9 doses) or indomethacin Continus (75 mg twice daily; 9 doses). A venous blood sample was also taken during each treatment period for subsequent determination of alpha 1-glycoprotein, and for drug assay. 3. Gastric bleeding on placebo was 1.4 (0.7-2.8) microliters 10 min-1 (mean, 95% confidence interval). Both aspirin and the indomethacin preparations caused significantly more bleeding (P less than 0.05). Rates of bleeding after aspirin, indomethacin BP, Indocid-R, and indomethacin Continus were respectively 22.0 (10.7-47.2) microliters 10 min-1, 4.4 (2.2-9.1) microliters 10 min-1, 10.8 (5.3-22.3) microliters 10 min-1, and 5.1 (3.0-10.6) microliters 10 min-1. 4. Rates of bleeding after indomethacin BP and indomethacin Continus, but not Indocid-R, were significantly less than after aspirin (P less than 0.01). 5. Salicylate or indomethacin was detectable in the plasma of all subjects after the active treatment periods, except for one instance involving a subject allocated indomethacin BP. Indomethacin levels were significantly higher 2 h after Indocid-R than with indomethacin BP or indomethacin Continus. 6. alpha 1-acid glycoprotein levels were not significantly affected by prior treatment with aspirin or indomethacin.

Adolescent↗
PubMed1994

Effect of sodium deoxycholate on the dissolution and absorption of copper-indomethacin and zinc-indomethacin.

The effects of sodium deoxycholate on the dissolution of indomethacin metal complexes were investigated. At pH 7.2, the dissolution of copper-indomethacin was very slow, while the dissolution of zinc-indomethacin was higher but less than that of indomethacin. In the presence of 5 mg of sodium deoxycholate, the dissolution of copper-indomethacin and zinc-indomethacin was significantly enhanced. The absorption of zinc-indomethacin in the rat jejunum was low, but that of copper-indomethacin was high, as compared to indomethacin. The addition of 0.2% sodium deoxycholate significantly enhanced the jejunal absorption of zinc-indomethacin in the rat, but did not increase the absorption of copper-indomethacin. Results indicated that the in vivo absorption behavior of zinc-indomethacin was predictable by in vitro dissolution, but such correlation was not applicable to copper-indomethacin. The absorption of copper-indomethacin was similar to that of indomethacin, in spite of its poor dissolution.

Animals↗
PubMed1989

Influence of indomethacin amphoteric gel on gastric ulcerogenicity and absorption of indomethacin in rats.

Indomethacin is a potent and efficacious antiinflammatory agent. However, a limiting side effect is its ability to cause gastric ulceration. This study was designed to investigate the effects of an amphoteric gel on the gastric ulcerogenicity and pharmacokinetics of indomethacin. Oral administration (5 mg/kg) in a suspension and a gel formulation were compared to an intravenous (iv) formulation of indomethacin in rats. The iv formulation administered to rats produced large severe ulcers in some rats but not in others. In contrast, the oral suspension produced small ulcers in all rats. The difference in toxicities is attributed to a centrally mediated action as a result of high plasma levels of indomethacin following iv administration, compared to locally mediated action with the suspension, resulting from local high concentrations of indomethacin on the apical epithelial surface because of the presence of indomethacin crystals. Oral administration of the gel formulation did not result in any gastric ulceration and improved the bioavailability of indomethacin to 115.5%, compared with 68.2% for the suspension. The reduced gastrointestinal toxicity of indomethacin in the gel was attributed to the gel's ability to dissolve indomethacin, preventing the localized high concentration observed with the suspension and possibly providing a gastric protectant phospholipid. The gel formulation doubled the oral bioavailability and the tmax of indomethacin compared to the suspension but did not affect the half-life. The results indicate that the local irritant effect of indomethacin, in rats, can be reduced by appropriate formulation design and suggest that the ulcerogenicity index for indomethacin can be improved by the use of an amphoteric gel formulation.

Administration, Oral↗
PubMed1999

Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl-acetate) in relation to indomethacin crystallization.

PURPOSE: To measure solid-state features of amorphous molecular dispersions of indomethacin and various molecular weight grades of poly(vinylpyrrolidone), PVP, and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA, in relation to isothermal crystallization of indomethacin at 30 degrees C. METHODS: The glass transition temperatures (Tg) of molecular dispersions were measured using differential scanning calorimetry (DSC). FT-IR spectroscopy was used to investigate possible differences in interactions between indomethacin and polymer in the various dispersions. The enthalpy relaxation of 5%w/w and 30%w/w polymer dispersions was determined following various aging times. Quantitative isothermal crystallization studies were carried out with pure indomethacin and 5%w/w polymers in drug as physical mixtures and molecular dispersions. RESULTS: All coprecipitated mixtures exhibited a single glass transition temperature. All polymers interacted with indomethacin in the solid state through hydrogen bonding and in the process eliminated the hydrogen bonding associated with the carboxylic acid dimers of indomethacin. Molecular mobility at 16.5 degrees C below Tg was reduced relative to indomethacin alone, at the 5%w/w and 30%w/w polymer level. No crystallization of indomethacin at 30 degrees C was observed in any of the 5%w/w polymer molecular dispersions over a period of 20 weeks. Indomethacin alone and in physical mixtures with various polymers completely crystallized to the y form at this level within 2 weeks. CONCLUSIONS: The major basis for crystal inhibition of indomethacin at 30 degrees C at the 5%w/w polymer level in molecular dispersions is not related to polymer molecular weight and to the glass transition temperature, and is more likely related to the ability to hydrogen bond with indomethacin and to inhibit the formation of carboxylic acid dimers that are required for nucleation and growth to the gamma crystal form of indomethacin.

Calorimetry, Differential Scanning↗
PubMed1994

Pharmacokinetics of indomethacin octyl ester (prodrug) and indomethacin produced from the prodrug.

A prodrug of indomethacin, indomethacin octyl ester (IM-OE), was synthesized and its pharmacokinetics was investigated in rat. To describe the time course of the plasma indomethacin and IM-OE after intravenous (iv) and oral administrations, a pharmacokinetic model with four compartments was developed. Indomethacin rapidly appeared in plasma after iv administration of IM-OE and declined in a monoexponential manner, with a rapid decline and low plasma levels of IM-OE. The plasma concentrations of indomethacin after oral administration of IM-OE were much lower than those after oral administration of indomethacin. The high concentrations of IM-OE compared with indomethacin were detected in liver 3 h after oral dosing of the prodrug, although IM-OE was not detected in plasma. A good fit was obtained between the observed and calculated curves based on the model, which includes a conversion rate constant of IM-OE to indomethacin for both iv and oral dosings of IM-OE. Additionally, the model could successfully describe the plasma concentration versus time profiles after indomethacin dosings.

Administration, Oral↗
PubMed1981

Pharmacokinetics of indomethacin in the neonate. Relation of plasma indomethacin levels to response of the ductus arteriosus.

To identify factors affecting the efficacy of indomethacin in closing symptomatic patent ductus arteriosus (PDA), we studied the pharmacokinetics of intravenous indomethacin, 0.2 mg per kilogram of body weight, in 35 premature infants with symptomatic PDA. Most infants responded to indomethacin with ductus constriction. Indomethacin infusions that were ineffective (seven doses in six patients) were associated with significantly faster clearance, a shorter half-life, and lower plasma levels (p less than 0.05). Six infants had later reopening of the ductus. All six received indomethacin in the first postnatal week; they could not be distinguished from infants with permanent closure on the basis of indomethacin kinetics, but they were of low gestational age. There was a 20-fold variation in plasma indomethacin levels 24 hours after a dose. In view of this variation and the relation between plasma levels and ductus constriction, we suggest that measurement of the plasma indomethacin level could be of value in infants with no response to a first dose.

Ductus Arteriosus↗
PubMed1996

Inhibitory effect of indomethacin on neonatal lung catabolism of prostaglandin E2: possible mechanism of the re-opening of the ductus arteriosus after indomethacin therapy.

Indomethacin has been used to treat patent ductus arteriosus (PDA). Re-opening of the ductus arteriosus (DA) after indomethacin therapy, however, is common, although the reason is unclear. Patency of the ductus arteriosus is thought to be maintained primarily by the vasodilatory effect of PGE2 in fetuses and neonates. The enzyme, 15-hydroxy prostaglandin dehydrogenase (15-PGDH) catalyzes the initial reactions converting the biologically active PGE2 to its inactive metabolite 15-keto-PGE2, and the lungs are a major site of this inactivation. In the present study, the effect of prenatal indomethacin treatment on the activity of neonatal rat lung 15-PGDH, and the effect of prenatal indomethacin on the re-opening of the DA induced by PGE2 were examined in rats. Indomethacin treatment at 3 mg/kg/day from day 18 to day 20 of gestation significantly decreased the activity of 15-PGDH in neonatal lungs. In a subsequent experiment, subcutaneous injection of PGE2 (4 micrograms) was given to newborn rats 3 hr after Cesarean delivery from pregnant females administered indomethacin (1, 3 mg/kg/day) as in the above experiment. The ratio of the DA to pulmonary artery was determined at intervals after injection. Maternal indomethacin treatment significantly increased the re-opening of the DA and prolonged the duration of re-opening induced by PGE2. These results suggest that the decrease in the catabolism of PGE2 in the lung is partly responsible for the failure of indomethacin therapy for PDA.

Animals↗
PubMed1984

Reduction of carcinogenicity of N-nitrosomethylurea by indomethacin and failure of resuming effect of prostaglandin E2 (PGE2) against indomethacin.

Nonsteroid antiinflammatory drugs such as indomethacin may play an important role in preventing the development of chemically induced experimental carcinomas of various organs including the large bowel in rats and mice. This effect might correlate with an inhibition of prostaglandin (PG) synthesis by these drugs. Sprague-Dawley rats were given three intrarectal doses of 4 mg N-nitrosomethyl-urea (MNU) within week 1 to induce large-bowel carcinomas. The experimental groups of rats received a 0.001% aqueous solution of indomethacin ad libitum as drinking water for days 1-8 and/or a subcutaneous injection of 500 micrograms/kg body weight of PGE2 immediately before and 2 h after each MNU dose. They were then maintained on basal diet and plain tap water without further treatment. At autopsy at week 31, the tumor incidence and the mean number of tumors per rat were 90% and 1.7 in untreated rats, 67% and 0.8 in indomethacin-treated rats, and 79% and 1.2 in indomethacin + PGE2-treated rats, respectively. The data indicate that indomethacin reduced the number of large-bowel tumors, while pharmacologic doses of PGE2 failed to reestablish the anticarcinogenic activity of indomethacin. It was concluded that a tolerable therapeutic dose of indomethacin can reduce the carcinogenic activity of MNU in the large bowel.

Animals↗
PubMed2003

Indomethacin responsiveness of patent ductus arteriosus and renal abnormalities in preterm infants treated with indomethacin.

OBJECTIVES: We evaluated the factors related to indomethacin responsiveness of the patent ductus arteriosus (PDA) and subsequent renal and electrolyte abnormalities in a large number of low birth weight infants. METHODS: The ductus was evaluated by Doppler echocardiogram or clinical signs after the last administration of indomethacin for 2538 low birth weight infants, through the use of postmarketing surveillance data. RESULTS: Multivariate logistic regression analyses demonstrated that clinical closure of PDA was significantly associated with pregnancy-induced hypertension and respiratory distress syndrome. In contrast, a 1-point increase of cardiovascular dysfunction score or a 1-day increase in postnatal age at the first indomethacin treatment decreased the responsiveness of the ductus to indomethacin. Clinical ductal reopening was significantly less likely to occur for each week of increased gestational age. Ductal reopening was more likely for each day of postnatal life at the first administration of indomethacin. Infants with preexisting renal and electrolyte abnormalities and infants whose mothers had received indomethacin tocolysis or who had chorioamnionitis were at increased risk of development of renal impairment. CONCLUSIONS: Both antenatal and postnatal factors predict good or poor response to indomethacin therapy for PDA.

Cardiovascular Agents↗
PubMedDate not supplied

Indomethacin disposition and indomethacin-induced platelet dysfunction in premature infants.

Indomethacin failed to produce permanent ductal closure in any of four premature infants with patent ductus arteriosus to whom the drug was given. Indomethacin half-lives measured in two premature infants were 21 and 24 hours, respectively, much longer than in full-term newborns or adults. Platelet function, as measured by platelet aggregation, was grossly abnormal for two to four days after indomethacin administration, normal values returning only by the ninth and tenth days. Gastrointestinal bleeding and transient renal dysfunction occurred in one infant. Measurement of plasma indomethacin concentrations in sick, low-birthweight infants could help guide indomethacin dose and dosage interval, prevent drug accumulation, and reduce toxicity. Further studies of potential toxicity seem to be indicated before instituting widespread indomethacin administration for ductal closure in premature infants.

Blood Platelet Disorders↗
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↗