Prostaglandin-like inhibitors of prostaglandin-H-synthase

The effect of none prostaglandin-like cyclopentanone derivatives on the prostaglandin H synthase activity was studied. Seven substances proved to be inhibitors of the enzyme, some of the being similar to the well-known nonsteroid antiinflammatory drugs with respect to their inhibitory activity.     

Experimental study of the interaction of nonsteroidal anti-inflammatory agents--voltaren and acetylsalicylic acid--with beta-adrenoblockers

It has been demonstrated in rat experiments that the beta-adrenoblockers propranolol and pindolol differ in the influence on the therapeutic and toxic effects of voltaren and acetylsalicylic acid. Propranolol has an analgetic action of its own, reducing the analgetic and antiinflammatory effects of voltaren and acetylsalicylic acid. It potentiates the antipyretic effect of voltaren and ulcerogenic action of both nonsteroidal antiinflammatory drugs. Pindolol exerts both analgetic and antiinflammatory action and does not affect the antipyretic effect of voltaren and ulcerogenic action of nonsteroidal antiinflammatory drugs. The difference in the action of the beta-adrenoblockers under study is likely to be linked with the characteristics of their pharmacological action spectrum.     

Imidazoles in the treatment of ocular mycoses

The use of a new class of broad spectrum antifungal drugs i.e. imidazoles and in particular ketoconazole in treatment of severe affections of the eye such as mycoses is described. The clinical trials included 40 patients with various forms of mycosis: mycotic canaliculitis (6 patients), mycotic blepharitis (4 patients), mycotic conjunctivitis (7 patients), keratomycosis (17 patients) and mycotic endophthalmitis (6 patients). Ketoconazole was used in the form of tablets and instillations. The combined treatment included nonsteroid antiinflammatory drugs and antibacterial agents. The clinical trials showed that ketoconazole had pronounced antifungal activity and was rather efficient in treatment of ocular mycoses. Its broad spectrum and low toxicity were recorded.     

Inhibition of angiotensin-induced contractions of guinea-pig isolated ileum by high concentrations of non-steroidal antiinflammatory drugs and various steroids and its reversal by prostaglandin E1

Nine non-steroidal antiinflammatory drugs, five steroidal antiinflammatory drugs and four sex steroids were found to potently and reversibly inhibit angiotensin-induced contractions of guinea-pig isolated ileum. The effects of these drugs were reversed by small amounts of PGE₁ but the mechanism of their action was probably non selective for angiotensin.     

Changes in the filtration and reabsorption barrier of the kidneys of the rat after administration of nonsteroidal anti-inflammatory preparations

Nonsteroid antiinflammatory preparations, influencing biosynthesis of renal prostaglandins, are able to produce certain changes in hemodynamics of the organ with successive ischemia. Administration of these preparation (indomethacin and voltaren) to rats in doses corresponding to human therapeutic ones, produces dystrophic changes in the canalicular epithelium of the nephron and appearance of infiltrates in the interstitium and in the lamina propria of the renal calyxes mucous membrane. Intercellular edema and changes in configuration of the cells, decreasing electron density of hyaloplasm, swelled mitochondria, diluted cysterns of the Golgi complex and of the endoplasmic reticulum--are general regularities in ultrastructural reorganization of the cells in response to administration of the two preparations. These changes differ only in degree of their manifestation. As demonstrate the results, the pharmacologic depression of the prostaglandin synthesis causes decreased blood supply of the kidneys and successive depression of their functional state. This can be considered as risk factors of the renal complications under treatment with the nonsteroid antiinflammatory preparations.     

Depside as potent inhibitor of prostaglandin biosynthesis: a new active site model for fatty acid cyclooxygenase

Forty depsides and depsidones, the esters of phenolcarboxylic acids, were examined for their inhibitory effect against prostaglandin biosynthesis with rabbit renal microsomes. 4-0-Methylcryptochlorophaeic acid was the most active inhibitor so far tested and its IC50 value was 0.34 muM. Kinetic investigation has shown that this depside acts competitively with respect to arachidonic acid as most of the non - steroidal antiinflammatory drugs. X-Ray analysis has revealed that 4-0-methylcryptochlorophaeic acid maintains its rigid conformation by forming a strong hydrogen bond between the hydroxyl and methoxyl groups. Comparison of CPK models between 4-0-methylcryptochlorophaeic acid and non-steroidal antiinflammatory drugs revealed that the carboxyl group and the two rings of these drugs are almost superimposable to those of the depside. This finding led us to propose a new active site model based on the three dimentional structure of the depside.     

In vitro inhibition of prostaglandin production by azathioprine and 6-mercaptopurine

Although there are many data concerning the cytotoxic and immunosuppressive effects of antimetabolites such as azathioprine and 6-mercaptopurine, the mechanism of their antiinflammatory action has not been extensively investigated. In the present work, it is shown that azathioprine and 6-mercaptopurine (10-500 micrograms/ml) inhibit in a dose-dependent manner the production of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 by unseparated spleen cells as well as that of 6-keto-PGF1 alpha by adherent peritoneal macrophages. This inhibitory effect appears rapidly in vitro (within 15 min of incubation) and is observed in the presence of exogenous arachidonic acid (5 x 10(-6) M). The persistence of this effect in the presence of arachidonic acid, together with the fact that the production of four cyclooxygenase derivatives of acid arachidonic metabolism are inhibited, suggests that these drugs are acting at the cyclooxygenase level. The finding that cytotoxic and immunosuppressive agents, which act mainly by inhibiting RNA and DNA synthesis, can block prostaglandin production, may explain part of their antiinflammatory effects.     

A new side effect of BCG immunotherapy — BCG-induced arthritis in man

Summary Ten of 159 patients showed arthritic symptoms during the course of BCG immunotherapy for advanced cancer. The arthritic symptoms occurring after BCG injections had the following characteristics: (1) The incidence of arthritis was closely correlated with the host immunologic responsiveness to BCG; (2) These symptoms usually occurred 1–5 months after the first BCG injection (7/10); (3) The arthritic symptoms usually started with morning stiffness (9/10), which was followed by acute inflammatory signs in the affected joints. They gradually subsided in response to treatment with nonsteroid antiinflammatory drugs, but were not completely cured while the effectiveness of BCG continued; (4) The symptoms were aggravated by additional BCG injections (8/10). (5) This form of arthritis could be differentiated from rheumatoid arthritis, tuberculous, or purulent arthritis by its clinical course and by roentgenograms of the affected joints. It is thought to be induced by the adjuvant effect of BCG, and is a new side effect of BCG immunotherapy.     

Effects of meconic and comenic acids on slow sodium channels of secondary neurons

Effects of comenic and meconic acids on cultured dorsal root ganglion cells were investigated by the whole-cell patch clamp technique. The acids, having a well-known antiinflammatory and antibacterial action, decreased effective charge transfer in the activation gating system of TTX-resistant (slow) sodium channels in a dose-dependent manner. The effects were described by Hill's equation. The dissociation constant and Hill coefficient values were K(D) = 100 nM and X = 0.5 (for comenic acid) and K(D) = 10 nM and X = 0.34 (for meconic acid). The nonspecific antagonist of opioid receptors naltrexone totally blocked the effects. We suggest that the acids studied activate a subpopulation of opioid receptors negatively coupled to TTXr sodium channels.     

Soybean lipoxygenase inhibition by nonsteroidal antiinflammatory drugs

Eighteen known nonsteroidal antiinflammatory drugs (NSAID) were tested for their action against soybean lipoxygenase (E.C.1.13.11.12) using linoleic acid as substrate. It was found that the best inhibitors of lipoxygenase were naproxen, BW 755C, indomethacin and isoxicam. Drugs with intermediate potency were meclofenamic acid, phenyl-butazone and benoxaprofen. Other drugs such as ibuprofen and zomepirac were only weakly active in the test.     

Coenzyme A esters of 2-aryloxyphenoxypropionate herbicides and 2-arylpropionate antiinflammatory drugs are potent and stereoselective inhibitors of rat liver acetyl-CoA carboxylase.

The CoA esters of diclofop, haloxyfop and fluazifop are up to 425-fold more potent than the corresponding unconjugated herbicides as inhibitors of rat liver acetyl-CoA carboxylase (EC 6.4.1.2); the most potent inhibitor is (R)-fluazifopyl-CoA2 (Ki = 0.03 microM). The binding site is stereoselective for (R)-diclofop, the herbicidally active enantiomer, and for (R)-diclofopyl-CoA. The CoA esters of the antiinflammatory drugs ibuprofen and fenoprofen also strongly inhibit this carboxylase. (S)-Ibuprofenyl-CoA (Ki = 0.7 microM), the CoA ester of the enantiomer with antiinflammatory activity, is 15-fold more potent as an inhibitor than (R)-ibuprofenyl-CoA. These results suggest that some of the biological effects of these herbicides and antiinflammatory drugs in animals may be due to the inhibition of acetyl-CoA carboxylase by their acyl-CoA derivatives.     

Possible interactions between neurotensin and prostaglandins in the isolated rat portal vein

Neurotensin (NT) was found to elicit a dose-dependent contractile effect in the isolated rat portal vein. This effect was not inhibited by phentolamine, atropine, methysergide, a mixture of diphenhydramine and cimetidine, or by [Leu⁸]-angiotensin II, but it was markedly reduced or abolished by various antiinflammatory drugs such as indomethacin, acetylsalicylic acid, mefenamic acid, hydrocortisone and by mepacrine, an inhibitor of phospholipase A₂. The concentrations of antiinflammatory drugs used to inhibit NT, also antagonized the venoconstrictor effects of bradykinin and angiotensin, but did not affect the responses of the vein to noradrenaline. [D-Trp¹¹]-NT, a previously described NT antagonist, was found to inhibit selectively and dose-dependently the stimulant effect of NT in the portal vein. The results suggest the existence of specific receptors for NT in the isolated rat portal vein. The response of this tissue to NT, and possibly to other peptides, appears to be dependent upon the presence of a functional PG biosynthetic pathway.     

Effects of nonsteroidal antiinflammatory drugs on the proton exchange reaction between octanol and water: its correlation with their inhibitions of inflammation and prostaglandin synthesis

Effect of various antiinflammatory drugs on proton exchange between octanol OH and water after partition equilibrium between octanol and water at pH 7.4 was examined. These drugs accelerated the proton exchange reaction to different extents. The rate constant of the proton exchange induced by the drugs was well correlated with their biological potencies in inhibiting Carrageenan-induced edema and prostaglandin synthesis, suggesting that proton or electron movement in an apolar environment is very important for exhibition of these biological effects.     

Enantiomeric separation of drugs and herbicides on a beta-cyclodextrin-bonded stationary phase.

A chemically bonded beta-cyclodextrin chiral stationary phase for HPLC was prepared in a "one pot" process by the reaction of a phenylated beta-cyclodextrin with silica gel. Various racemic analytes such as drugs (aminoalcohol adrenergic beta-blockers, benzodiazepine anxiolytics, arylpropionic acid antiinflammatory agents) and herbicides (aryloxypropionic acids and esters) were separated on the prepared material. The column showed good chiral recognition ability for most of the solutes tested when using heptane and either 2-propanol or chloroform as organic mobile phase modifiers.     

Effect of non-steroidal anti-inflammatory agents on interferon induction]

Nonsteroid antiinflammatory agents (NAIA) such as antipyrine, butadion, acetylsalicylic acid, sodium salicylate, stampyrine and 4-iodantipyrine are not interferonogenic. Still, they stimulated interferonogenic action of poly(G).poly(C) in studies on animals. Relation between the interferon-stimulating action of the NAIA and their effect on activity of prostaglandin and the influence on the immune system was suggested.     

Antiinflammatory action of hydrosoluble dimethyltriazenes on the carrageenin-induced edema in guinea pigs

The antiinflammatory activity of three hydrosoluble aryldimethyltriazenes has been examined on the carrageenin induced edema in guinea pig. The administration of equitoxic dosages of p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK) and p-(3,3-dimethyl-1-triazeno)sulfonic acid sodium salt (DM-SO3Na) 1 h after carrageenin application, causes 4 h later a similar and statistically significant reduction of paw swelling by about 40% whereas, p-alanylphenyl-3,3-dimethyl-1-triazeno (DM-ALA(OH)) is inactive. Of the two active compounds, DM-COOK displays interesting properties, being rapidly active and causing a peak of inhibition higher than that caused by DM-SO3Na. The antiinflammatory activity of DM-COOK is comparable with that caused by 5 mg/kg indomethacin and 200 mg/kg phenylbutazone. However, DM-COOK, unlike indomethacin, causes an inhibition of leukocyte migration into the peritoneal cavity induced by casein treatment, thus indicating a different mechanism of action. This effect needs clarification and seems not to be correlated to cytotoxicity of the drug for migrating white blood cells, as evidenced by "in vitro' examination.     

Effect of high concentrations of non-steroidal and steroidal antiinflammatory drugs on prostaglandin-induced contractions of the guinea-pig isolated ileum

In addition to their well-known effect at low concentrations on prostaglandin synthesis or their release and production, 11 non-steroidal antiinflammatory drugs and 4 antiinflammatory steroids exhibit at high concentrations a direct antagonism on certain prostaglandin actions. This is demonstrated on PGE₁-and PGF_2α-induced contractions of guinea-pig isolated ileum when compared to acetylcholine-induced contractions. This inhibitory effect is totally reversible after washing out the drugs from the organ bath.     

Pain relieve after impacted wisdom teeth extraction dependent on the drug therapy

Purpose of this study was to compare the effects of combined therapy using nonsteroid anti-inflammatory analgetics and corticosteroids, and the effects of the mono-therapy with same drugs for post-operative pain after surgical removal of the impacted mandibular third molar. The study was completed at the Department of Oral Surgery and at the Department of Dental Medicine of the Public Institute Health Center Zenica in Zenica. The research included 60 patients divided into 3 groups using random selection, including both sexes. Age range was between 18 and 45 years. All participants came without any pain or other inflammatory symptoms at the time of oral surgical intervention. Two medicaments were prescribed after the impacted tooth removal: 15 mg of nonsteroid anti-inflammatory analgesic drug (Meloxicam, Bosnalijek, BiH) and 32 mg Methylprednisolone (corticosteroid, Bosnalijek, BiH). Both medicaments were applied per os, according to schedule determined by the research protocol. The level of post-surgical pain was evaluated by the 1-10 visual analog scale (VAS). One way ANOVA was made with Tuckey post-hoc tests. Statistically significant difference (p < 0.05) was found between the group treated with mono therapy and the group treated with combined therapy. Application of monotherapy using only corticosteroids or only nonsteroid anti-inflammatory pain-killers was less effective compared to the combined therapy with both medicaments after surgical removal of the impacted mandibular third molar.     

Effects of adlay hull extracts on uterine contraction and Ca2+ mobilization in the rat

Dysmenorrhea is directly related to elevated PGF(2alpha) levels. It is treated with nonsteroid antiinflammatory drugs (NSAIDs) in Western medicine. Since NSAIDs produce many side effects, Chinese medicinal therapy is considered as a feasible alternative medicine. Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) has been used as a traditional Chinese medicine for treating dysmenorrhea. However, the relationship between smooth muscle contraction and adlay extracts remains veiled. Therefore, we investigated this relationship in the rat uterus by measuring uterine contraction activity and recording the intrauterine pressure. We studied the in vivo and in vitro effects of the methanolic extracts of adlay hull (AHM) on uterine smooth muscle contraction. The extracts were fractionated using four different solvents: water, 1-butanol, ethyl acetate, and n-hexane; the four respective fractions were AHM-Wa, AHM-Bu, AHM-EA, and AHM-Hex. AHM-EA and its subfractions (175 microg/ml) inhibited uterine contractions induced by PGF(2alpha), the Ca(2+) channel activator Bay K 8644, and high K(+) in a concentration-dependent manner in vitro. AHM-EA also inhibited PGF(2alpha)-induced uterine contractions in vivo; furthermore, 375 microg/ml of AHM-EA inhibited the Ca(2+)-dependent uterine contractions. Thus 375 microg/ml of AHM-EA consistently suppressed the increases in intracellular Ca(2+) concentrations induced by PGF(2alpha) and high K(+). We also demonstrated that naringenin and quercetin are the major pure chemical components of AHM-EA that inhibit PGF(2alpha)-induced uterine contractions. Thus AHM-EA probably inhibited uterine contraction by blocking external Ca(2+) influx, leading to a decrease in intracellular Ca(2+) concentration. Thus adlay hull may be considered as a feasible alternative therapeutic agent for dysmenorrhea.     

Radical scavenging as the mechanism for stimulation of prostaglandin cyclooxygenase and depression of inflammation by lipoic acid and sodium iodide.

Certain radical-trapping reducing agents have been shown to stimulate prostaglandin biosynthesis in vitro (1--6) and to depress phorbol myristate acetate-induced mouse ear edema (16). The increased prostaglandin synthesis resulted from influences on the cyclooxygenase. To ascertain whether these alterations were due to direct interaction with the enzyme or to indirect scavenging of the oxidant released during PGG2 reduction, we report the effects of lipoic acid and sodium iodide. Both of these agents stimulated the enzymatic oxygenation of arachidonic acid, increased the reduction of PGG2 to PGH2, quenched the EPR signal induced by arachidonic acid and depressed mouse ear edema. In addition to discovering two unusual antiinflammatory agents, we have confirmed that materials with entirely different structures can have identical effects on the cyclooxygenase, suggesting indirect stimulation of this enzyme due to trapping of the oxidant.