Indomethacin: Plasma concentrations and protein binding in man

Summary The fluorometric method of Holt & Hawkins (1965) has been modified to permit determination of 50 ng indomethacin in 0.5 ml plasma, by measuring its fluorescence in a phosphate buffer at pH 11.6 instead of sodium hydroxide. The method has also been adapted to show the presence of salicylic acid and a column chromatographic method has been devised for its removal. The protein binding of indomethacin in human plasma was calculated to be about 90% from an association constant of 0.86×10³ M^–1 (M=molarity). The number of binding sites on albumin is about 15. The plasma levels of indomethacin in patients receiving continuous treatment with Indocid^® were between 0.5 and 3 µg/ml during the 4–5 h immediately after the last dose of 25 mg. The disappearance of indomethacin from plasma appears to consist of a fast primary phase at plasma concentrations greater than 1 µg/ml (T 1/2 about 90 min.), and a slower secondary phase.     

Effect of sustained release on the pharmacokinetic profile of indomethacin in man

The effect of sustained release on the pharmacokinetic profile of indomethacin was examined by comparing to three reference regimens: an intravenous dose, a single 75 mg dose of conventional capsules, and three 25 mg conventional doses given at 4-h intervals. Results indicate that the sustained release test formulation exhibited more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion, and showed an overall bioavailability of 0.93 (95 per cent C.I. = 0.82, 1.04) relative to three 25 mg doses of the conventional capsules.     

Effect of indomethacin on water intake of the rat

Indomethacin stimulated water intake in intact rats. This effect could also be demonstrated in bilaterally ureteral ligated rats, but it was totally abolished after bilateral nephrectomy. It is suggested that the stimulatory effect of indomathacin on water consumption is mediated by a renal factor.     

唾液皮质醇与血浆皮质醇、尿游离皮质醇测定的相关性分析及其临床价值

目的探讨正常人唾液皮质醇、血浆皮质醇和24 h尿游离皮质醇三者之间的相关性。方法选择30例健康受试者同时检测唾液皮质醇、血浆皮质醇和24 h尿游离皮质醇。男子组和女子组各15例。采用化学发光技术测定,唾液标本采用唾液收集器收集,血标本为血浆,24 h尿液标本用硼酸防腐。结果唾液皮质醇和血浆、24 h尿液皮质醇在正常男女组之间均无显著性差异（P＆gt;0.05）,唾液皮质醇与血浆皮质醇（r=0.91）、唾液皮质醇与24 h尿游离皮质醇（r=0.95）,均存在显著的相关性。结论唾液皮质醇可作为库欣氏综合征的筛查指标。     

The effect of pirenzepine (LS 519), a specific antimuscarinic drug,on cortisol levels in man

The authors investigated the effect of a single 75-mg oral dose of pirenzepine, a drug which selectively blocks the muscarinic receptors and does not cross the blood-brain barrier, on the function of the HPA axis. A significant decrease in basal cortisol values following the administration of the drug was observed in comparison with a placebo test. Moreover, the adrenal response to exogenous adrenocorticotropin (ACTH) administration was unchanged following a 5-day course of the drug, ruling out direct action of pirenzepine at the adrenal level. These data suggest that cholinergic muscarinic hypothalamic and/or pituitary systems may be involved in the regulation of ACTH-cortisol secretion.     

Effect of prostaglandin E1 and its biosynthesis inhibitor indomethacin on drinking in the rat

In the rat, injection of prostaglandin E₁ (PGE₁)0.5, 1.0 or 2.0 μg into the 3rd brain ventricle (3rd b.v.) inhibited the water deprivation-induced water intake in a dose-related fashion. The 1.0 μg dose of PGE₁ also inhibited the intake of 1.8% sodium chloride in rats depleted of body sodium by intraperitoneal dialysis, and of food in food deprived rats during a 60 min test period. Prostaglandin E₁ (1 μg) depressed the dipsogenic effect of angiotensin II (AII) or carbachol injected through the same cannula. Water-deprived rats pretreated with the PG synthetase inhibitor indomethacin, in two different doses, showed enhanced water intake. The pretreatment with indomethacin also enhanced the dipsogenic effect of various doses of AII injected into the 3rd b.v. The antagonistic action of PGE₁ on water-deprivation, or AII-induced water intake, and the enhancement of water intake after blocking PGs synthesis, suggests the involvement of PG in the regulation of thirst.     

Studies on the inhibitory effect of indomethacin and meclofenamate on the adrenalectomy-induced increase in plasma renin concentration

Summary Bilateral adrenalectomy combined with a sodium-deficient diet caused a time-dependent increase in plasma renin concentration in rats. Seventy-two hours after adrenalectomy the inhibitors of prostaglandin biosynthesis indomethacin and meclofenamate diminished the plasma renin concentration by about 50%. This effect was independent of the amount of renin released. Indomethacin and meclofenamate fully retained their ability to reduce the plasma renin concentration when the renal sympathetic nerves or the macula densa cells of the kidneys no longer contributed to renin release. It is concluded that in adrenalectomized rats renal prostaglandins affect the baroreceptor-mechanism in the afferent arterioles and thus enhance renin release.Supported by DFG Me 541/2     

Naloxone decreases the inhibitory effect of alprazolam on the release of adrenocorticotropin/cortisol induced by physical exercise in man

AIMS

To establish the possible involvement of alprazolam (ALP) and/or opiates in the mechanism underlying the ACTH/cortisol response to physical exercise.

METHODS

Tests were carried out under basal conditions (exercise control test), exercise plus ALP (50 µg at time −90 min), naloxone (10 mg at time 0) or ALP plus naloxone. Plasma ACTH and serum cortisol concentrations were evaluated in blood samples taken before, during and after the bicycle ergometer tests.

RESULTS

ACTH and cortisol concentrations rose significantly after physical exercise. Maximum peak at time 15 min (P≤ 0.01 vs. baseline) for ACTH and at time 30 min (P≤ 0.01 vs. baseline) for cortisol. In the presence of naloxone, the ACTH and cortisol responses were significantly increased (maximum peak at time 20 min, P≤ 0.02 vs. control test for ACTH, and at time 30 min (P≤ 0.01 vs. baseline) for cortisol) whereas they were abolished by ALP. When ALP and naloxone were given together, the inhibitory effect of ALP was partial.

CONCLUSIONS

These data demonstrate an inhibitory effect of ALP in the regulation of the ACTH/cortisol response to physical exercise in man and suggest that GABAergic receptor activating benzodiazepines and opioids interact in the neuroendocrine secretion of ACTH/cortisol.     

Effect of indomethacin on cardiac beta-adrenergic receptors

Treatment of rats with indomethacin, 1.5 mg/kg per day, for one week, significantly reduced the number of beta-adrenoceptors in the heart without altering their affinity for the specific beta-adrenergic ligand. In indomethacin-treated rats there was a reduction in the cardiac response to epinephrine in vivo as indicated by a shift to the right of the epinephrine dose-heart rate response curve. These results support a possible interference by indomethacin in beta-adrenoceptor-mediated effects.     

The effect of an antacid on the bioavailability of indomethacin

Summary The biovailability of indomethacin from two indomethacin-antacid (aluminum hydroxide magnesium carbonate and magnesium hydroxide) combinations was compared with the bioavailability of oral indomethacin. Relative bioavailability was estimated by three methods: comparison of plasma concentrations at various times, comparison of areas under plasma concentration time curves, and comparison of the amount of drug excreted unchanged in the urine. A double blind three-way crossover study was conducted in twelve healthy volunteers. The combination with the slightly smaller amount of antacid (preparation A) showed significantly decreased bioavailability by all three methods in comparison with indomethacin alone (preparation C). The combination with the larger amount of antacid (preparation B) was also less bioavailable than preparation C. This effect was significant only for the comparison of areas under curves and not for plasma levels, although the mean plasma levels produced by preparation B at all times were lower than those for preparation C. These findings suggest that aluminum hydroxide magnesium carbonate and magnesium hydroxide decrease the bioavailability of indomethacin.A preliminary report has been published as an abstract in Clin. Res.23, 219, 1975     

Pharmacokinetics of intraarticular indomethacin in patients with osteoarthritis

Summary The pharmacokinetics of intraarticular indomethacin was evaluated in 10 patients with osteoarthritis in an open labelled, randomized, cross-over study. Each patient received a single dose of 10 mg indomethacin by the intraarticular and the intravenous routes with a seven-day interval between the injections. Blood was repeatedly collected and urine was collected for 24 h after dosing.Indomethacin was rapidly absorbed from the joint, giving a maximum serum concentration (C_max) of 0.60 g · ml^–1 approximately 1 h after dosing. The systemic bioavailability (f) was 80% and the mean absorption time (MAT) was about 2 h. The apparent terminal half-life and mean residence time (MRT) were 2.8 h and 4 h, respectively. The urinary recovery of total indomethacin (unchanged + glucuronides) was 24% of the dose and renal clearance (CL_R) was estimated to be about 21 ml · min^–1. The disposition of indomethacin after intravenous and intraarticular administration appeared to be similar.The results suggest that the intraarticular administration of indomethacin would not exclude the risk of developing untoward, systemic, concentration-dependent effects.     

吲哚美辛结肠定位凝胶微丸的研究

目的制备吲哚美辛凝胶微丸实现结肠定位给药。方法采用滴制法制备海藻酸钙微丸,以微球圆整度、包封率、载药量为质量指标,通过正交试验选出优化处方,并用丙烯酸树脂Eudragit S100进行包衣。结果凝胶微丸在人工胃液和人工肠液中6 h累积释放率小于15%,而在人工结肠液中2 h达80%以上。结论所制得的吲哚美辛凝胶微丸符合结肠定位的基本要求。     

Chitosan microspheres prepared by an aqueous process: Release of indomethacin

Chitosan microspheres loaded with indomethacin were prepared using only aqueous solvents. The influence of formulation variables on indomethacin content in the microspheres and time for release of 66.6% of indomethacin from the microspheres was investigated. Amongst various variables, the indoemthacin:chitosan ratio and amount of crosslinking agent were important. Response surfaces were generated to optimise the aqueous process with respect to these critical variables, in order to obtain maximum indomethacin loading and optimum t 66.6 .     

Plasma beta-endorphin,ACTH and cortisol secretion in man after nasal spray administration of calcitonin

Summary Beta-endorphin, ACTH and cortisol secretion were measured in twelve healthy adult males after nasal spray administration 200 IU salmon calcitonin.A significant increase in plasma beta-endorphin, from 19.2 ng/l under basal conditions to a peak of 27.1 ng/l at 30 min was recorded. Plasma ACTH and cortisol were not affected. In individual subjects the beta-endorphin level was increased in eight of the twelve, ACTH rose in three and cortisol did not change in any of them. The data indicate that calcitonin induced a beta-endorphin increase independent of enhanced corticotrophin-cortisol release.     

Influence of benzyl benzoate as oil core on the physicochemical properties of spray-dried powders from polymeric nanocapsules containing indomethacin

To prepare spray-dried powders of poly(D,L-lactic acid) (PLA) or poly-epsilon-caprolactone (P epsilonC) from colloidal suspensions containing indomethacin (IND) using benzyl benzoate (BnB), nanocapsules (NC) were prepared by nanoprecipitation. To select the best NC formulations, increasing drug concentrations were tested (1.0, 1.5, or 2.0 mg/mL). The particle size was measured by Nanosizer. Spray-dried powders (SDP) were prepared by addition of Aerosil 200 into suspensions of NC. IND was assayed by HPLC. Free IND was determined using an Ultrafree. NC-SPD were examined under SEM. The particle sizes of all formulations are in the sub-300 nm range and are IND-associated, with drug recovery close to 100%. After 1 month, the formulations with highest drug content (2.0 mg/mL) showed a decline of total quantity of IND. After spray-drying, IND recovery for SDP presented values above 100%, indicating that the drug was concentrated from loss of mass during the process. To verify the relationship of oil phase with this loss of mass, similar NC (IND 1.5 mg/mL) prepared with Miglyol 810 (MI) were spray-dried, and SEM analysis showed nanostructures adsorbed onto SiO2. Similar nano-structures were not visualized for NC samples prepared with BnB. A swelling experiment showed the complete dissolution of both polymer by the BnB, whereas for MI the polymer masses remained unchanged. In conclusion, BnB is a solvent for PLA and P epsilonC and this ester is entrained during spray-drying. Despite the use of BnB in formulations of NC, PLA, or P epsilonC, colloidal suspensions prepared with BnB could be micelles instead of nanocapsules.     

复凝聚法制备吲哚美辛缓释微囊的研究

目的:通过吲哚美辛微囊的制备研究,为吲哚美辛的缓释制剂提供科学依据。方法:以微囊的药物包封率为制备工艺优化指标,利用复凝聚法,通过正交实验得出微囊的最佳制备工艺条件。结果:该法所制备微囊的粒度分布在2.2~32.3μm之间,收率可达80%以上。结论:实验证明,吲哚美辛微囊比吲哚美辛片剂具有明显的缓释作用。     

Mechanism of ulcerogenic activity of indomethacin and oxyphenbutazone

K.P. BHARGAVA, M.B. GUPTA and K.K. TANGRI, tMechanism of ulcerogenic activity of indomethacin and oxyphenbutazone, European J. Pharmacol. 22 (1973) 191–195.The ulcerogenic activity of indomethacin and oxyphenbutazone in albino rats was dose dependent. The gastric ulcers produced by indomethacin and oxyphenbutazone were significantly reduced by pretreatment with phenoxy-benzamine, phentolamine and by prior bilateral adrenalectomy and spinal cord transection while imipramine pre-treatment potentiated their incidence. Mepyramine prevented the ulcerogenic activity of oxyphenbutazone but failed to prevent the ulcers produced by indomethacin. Pretreatment with 2-bromolysergic acid diethylamide (BOL-148). propranolol and atropine failed to protect the animals from the ulcerogenic activity of indomethacin and oxyphenbutazone. The mechanism of ulcerogenic activity of these compounds is discussed.     

Substituted aminoalcohol ester analogs of indomethacin with reduced toxic effects

Synthesis and evaluation of five different N,N-disubstituted aminoethanol ester derivatives of indomethacin bearing structural resemblance to the aminoethanol ester class of anticholinergics are reported herein. The anticholinergic activity was incorporated into the intact esters to overcome the gastric toxicity of indomethacin, not only by blocking the acidic functionality but also by decreasing gastric secretions and motility. These derivatives exhibited in vitro stability in buffers of pH 2.0 and 7.4 for 6 h and were readily hydrolyzed by human plasma esterases to liberate the parent drug. All the derivatives were significantly less irritating to the gastric mucosa than the parent drug. Though only two esters showed antiinflammatory activity similar to that of the parent drug at equivalent dose levels, all the esters were equipotent to indomethacin in the mouse acetic acid–induced writhing assay for analgesic action. The present evaluation indicates that the combined pharmacological properties of these ester derivatives may prove useful for design and development of novel gastric sparing antiinflammatory molecules with potentially important therapeutic applications.     

Solubility and stability of indomethacin in arginine-assisted solubilization system

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID).It is practically insoluble in water, which precludes its use in aqueous solution formulations. The effect of arginine on the solubility of indomethacin was investigated in this study. The solubility enhancement of indomethacin by the arginine was observed. Aqueous solution formulation and freeze-drying formulation using arginine as hydrotropes were developed and studied for physical and chemical stability. Freeze-drying is considered as a suitable formulation to enhance shelf life of indomethacin.