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We evaluated whether defibrotide, a single-stranded polydeoxyribonucleotide that enhances prostacyclin (PGI2) release from various isolated organs, could also release PGI2 from the rabbit kidney and prove effective against renal ischemic injury. Isolated perfused kidneys responded to defibrotide (100, 250 and 500 micrograms ml-1 min-1) with a dose-dependent release of immunoreactive 6-keto-PGF1 alpha (4-fold increase at highest dose), which was prevented by indomethacin pre-treatment. In vivo, venous blood withdrawn from heparinized rabbits (and representative of renal outflow) was conveyed over a collagen matrix, onto which platelets adhered and aggregated. Recording the weight increase of the matrix was used as a bioassay to follow the time-course of released PGI2. We observed that renal outflowing blood from defibrotide treated animals (50 mgKg-1 i.v.) displayed lower (P less than 0.05 versus controls) platelet activation, consistent with enhanced PGI2 release from the kidneys. Furthermore, the duration of this effect was longer lasting than that predicted from the known plasma half-life of the drug. After transient (30 min) occlusion of the renal arteries, glomerular filtration rate (GFR) dropped by about 50% (P less than 0.01) during the first reperfusion hour in control animals, with only mild recovery having occurred 4 h later. Defibrotide (16 mgKg-1 bolus + 16 mgKg-1h-1, i.v.) could not antagonize the initial impairment (40% GFR reduction), but allowed full recovery at the end of the observation period (P less than 0.05 vs controls). Indomethacin, instead, caused a dramatic reduction of GFR (70%) during early reperfusion, with no subsequent recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Nimesulide (4-nitro-2-phenoxymethane sulfonanilide, Aulin, Mesulid) is a non-steroidal anti-inflammatory compound which shows antihistaminic activity and inhibits the immune release of histamine. The antihistaminic activity of this compound is specific for H1-receptor and has been demonstrated on isolated strips of guinea-pig trachea and on histamine-induced multiphasic inotropic response in left atria of guinea pig electrically driven. The effect of nimesulide is of non competitive type and, at the concentration of 1 x 10(-5) mol/l, is nearly 2 time less potent than pyrilamine (mepyramine) at 1 x 10(-6) mol/l. Nimesulide (1.6 mumol/kg i.v.) inhibits both bronchoconstriction (69%) and TXB2 formation (93%) induced by histamine (0.05 mumol/kg i.v.) in anaesthetized guinea-pigs. In contrast indomethacin (1.6 mumol/kg i.v.) decreases the generation of TXB2 (89%) without affecting the enhancement in tracheal insufflation pressure induced by histamine. In actively sensitized guinea-pigs both nimesulide and indomethacin protect the animals from deadly anaphylactic crisis. The rise in tracheal pressure induced by the antigenic challenge is inhibited of 80% and 63% respectively by nimesulide and indomethacin (6.4 mumol/kg i.v.). At this dose the two compounds reduced of 90% approximately the immunological release of TXB2 in the circulation. The release of histamine, induced by the anaphylactic reaction caused in perfused lungs obtained from actively sensitized guinea-pigs, is lessened by nimesulide (EC50 = 3.06; fid. lim. 2.59-3.63 mumol/l) and potentiated by indomethacin (EC50 = 0.89; fid. lim. 0.67-1.17 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Photodynamic therapy (PDT) with porphyrins and red light is receiving increasing attention in the management of malignant tumours. At present PDT is primarily indicated for the treatment of superficial or early-stage lesions. At the Department of Radiotherapy and the First Institute of Surgery in Padova (Italy) more than 150 cases of tumours of different types have been treated using this technique. This paper briefly describes 21 cases of superficial oesophageal cancer. A complete response was observed in 11 of 21 cases. Radiation therapy appeared to be very effective as a salvage treatment of non-response patients.

Bamifylline, a 7-8 disubstituted theophylline derivative, reduces in a dose dependent way (1 x 10(-5) M, 1 x 10(-4) M and 1 x 10(-3) M) the release of histamine, TXB2 (measured also as TXA2-like material) and SRS-A (as LTD4-like material) during the immunological challenge of actively sensitized guinea-pig lungs perfused in vitro. Theophylline was significantly less potent than bamifylline and particularly, at the higher concentrations used (1 x 10(-3) M), bamifylline was 2.7 times more potent than theophylline in reducing the immunological release of histamine and 1.6 and 1.5 times more potent in inhibiting the production of TXB2 and SRS-A, respectively. These data suggest that the ability of the two xanthine derivatives to control the immunological release of histamine represents an important point in understanding the mechanism of their anti-anaphylactic activity.

1514 Background: Encouraging results have been obtained inlow grade glioma (LGG) patients (pts) following TMZ therapy at the standard schedule of 200 mg/m2 for five-days every 28 days. A continuous dose TMZ schedule leads to DNA repair enzyme AGAT level depletion in tumor cells. By removing TMZ-produced methyl adducts, AGAT contributes to the development of resistance to alkylating agents. Methods: Pts with a diagnosis of LGG received TMZ 75 mg/m2/d for 21 days every 28 days at clinical or radiological progression. MiniMax Simon’s design with P0=0.2, P1=0.4, α=0.1, β=0.1 was used and a sample size of 36 pts was planned. The primary end-point was to assess the response rate (RR=CR+PR), and the secondary end-point to investigate the correlations between 1p/19q deletions by FISH and MGMT promoter methylation by methylation specific PCR (MSP). Results: 22 oligodendroglioma (O), 4 oligoastrocytoma (OA) and 10 astrocytoma pts (A) were enrolled (median age of pts 47 years, range 24–69 years; median KPS 90, range 50–100). Eleven pts were pre-treated with radiotherapy; 5 (13.5%) had enhancing lesion at MRI scan. RR was 30.5% (11 PR), all RR being obtained in pts with non-enhancing lesions; 20 pts (55.5%) had disease stabilization; 8/11 responders were assessable for 1p/19 q deletions and, of these, 6 pts (75%) had combined 1p/19q deletion. Median PFS was 17.4 months (interquartile ranges, 9.3–25). PFS at 1 year was 73% (SE 8%). Preliminary data on molecular assessment are: 29 pts were assessable for 1p and 19q deletions, both being present in 19 pts (65.5%). 1p/19 q loss was significantly greater in pts with O/OA than A (p=0.01). Of 11 assessable pts, 7 (63.6%) presented MGMT promoter gene methylation and all 7 pts presented 1p and 19q deletions (p=0.03). Grade 3 lymphopenia was observed in 4 pts (11.1%) and 1 patient had G2 reversible renal toxicity. Conclusion: TMZ for 21 days every 28 is an active and well tolerated regimen in pts with LGG. The analysis to verify any correlation between molecular markers and clinical outcome is ongoing. [Table: see text]

A high plasma concentration of high density lipoproteins (HDL) is associated with a decreased risk for cardiovascular disease, an effect commonly attributed to the central role of HDL in reverse cholesterol transport, the process by which excess cholesterol in the arterial wall is transported to the liver for excretion. Nevertheless, HDL exert additional cellular effects, like stimulation of prostacyclin release, that may well contribute to the protection of the arterial wall in conditions not associated with increased lipid deposition. This prompted us to investigate the direct protective effect of HDL against postischemic myocardial dysfunction in an isolated heart model. Rat hearts were perfused at a constant flow of 15 mllmin for 30 min; a moderate ischemia was induced by reducing the flow to 1 mllmin for 20 min and was followed by a 30 min reperfusion at 15 ml/min. Buffer-perfused hearts showed a clear-cut reduction of left ventricular function with a substantial increase of coronary resistance, associated with a consistent release of CK in the perfusates. The perfusion of the hearts with human HDL during the last 10 min of pre-ischemia caused a dosedependent protection against ischemia-reperfusion damage, as shown by an almost complete recovery of lefl ventricular developed pressure, a minimal increase of coronary perfusion pressure and a blunted CK release. Synthetic HDL containing lecithin and apoA-I were also effective in preventing ischemiareperfusion injury, whereas lipid-free apoA-I and lecithin liposomes were totally ineffective. These findings indicate that HDL exert a direct protective effect against ischemia-reperfusion damage, providing support to the therapeutic use of synthetic HDL in a variety of clinical conditions characterized by myocardial stunning, e.g., thrombolytic therapy, angioplasty or cardiac surgery.

Stereoselective synthesis and biological properties of PAF-acether, its enantiomer and some analogues of both are reported. The results clearly indicate that the ONIUM SIZE and SHAPE of the various compounds tested are important in determining guinea-pig bronchoconstriction and human platelet aggregation.

Analgesia and locomotor activity are genetically differentiated in C 57 and DBA mice. In fact, DBA strain, unlike C 57, is very sensitive to the analgesic effects of morphine. On the contrary, morphine elicits an increase of locomotor activity only in C 57 mice. We have used this genetic approach to study the in vitro response of vas deferens contractions to morphine and methionine-enkephalin. The results obtained are the following: 1. The percentage of morphine inhibition of the electrically evoked contractions of the longitudinal muscle of the vas deferens is greater in DBA strain, which is sensitive to the analgesic effects of morphine, than in C 57 mice in which morphine exerts a stimulating effect of the locomotor activity; 2. Met-enkephalin has been found to be more active than morphine on the same preparation; 3. The inhibitory effects of Met-enkephalin appear to be greater in C 57 than in DBA mice; 4. Different doses of Naltrexone are required to reverse the effects of morphine and Met-enkephalin; 5. Cumulative doses of Met-enkephalin and morphine induce different responses in the vas deferens of C 57 and DBA mice. The results emphasize the usefulness to study analgesic activity in these strains of mice.

Seventeen agricultural male workers, aged between 21 and 56 years, were investigated in the field during six different job-activities of apple-farming: pruning, weeding, hand and mechanical spraying, mowing and picking. Pulmonary ventilation and oxygen consumption were recorded for short periods by Oxylog, while heart rate was monitored for more than 24 hours by Holter's method. The farmers also rated the work intensity according to Borg's RPE scale. Pulmonary ventilation ranged on average between 13 and 30 1/min and oxygen consumption between 500 and 1300 ml/min, with a relative aerobic cost between 15 and 40%, in the different work activities. Heart rate varied on average between 80 and 94 beats/min with a relative cardiac cost between 20 and 30%. The physiological criteria (oxygen uptake and cardiac response) and the subjective rating of fatigue gave a substantially similar evaluation of the work strain, ‘moderate-heavy’ for mowing, weeding and picking, ‘moderate’ for pruning and hand spraying, ‘light’ for mechanical spraying of pesticides. On the whole, apple-farming can be evaluated as ‘moderate’ intensity, thanks to the mechanisation implemented in reducing the work-load and the work-time of many job activities.

The relationship between structure and tracheal relaxing activity of cyclic-3′,5′-adenosine monophosphate (cAMP), cyclic-3′,5′-guanosine monophosphate (cGMP) and cyclic-3′,5′-inosine monophosphate (GIMP) derivatives has been studied. The results obtained indicate that the 8 position of the cyclic nucleotides plays an important role in the relaxing activity of these compounds. Experiments have also shown that the Bromo substitution of cGMP increases the tracehal relaxing activity both in vitro and in vivo .

A clinical experiment was carried out to study the effect of PGE1 (prostaglandin E1) on the isolated cat rabbit rat guinea pig and frog heart. Heart rate contraction and coronary flow were used as heart parameters in the study. Results showed differential effects of PGE1 on the different species. The effect was negative for cat and rabbit heart and modest in rat heart. On the other hand under the experimental conditions the effect of PGE1 on guinea pig and frog heart was strong. Effects on all the species are illustrated graphically. In the guinea pig a 1 ug dose of PGE1 caused a 10-minute increase in heart rate and increased heart contraction and coronary blood flow. The effects of PGE1 on the guinea pig heart were not prevented by beta-receptor blocking agents perfusion of Nethalide. The PGE1 effect on the frog heart was a long-lasting positive inotropic effect similar to that of adrenaline. The mechanism of the pronounced PGE1 action on the guinea pig and frog heart is still unknown. (Summaries in GER FRE)

Kinetic analysis of uptake of levo -metaraminol by rabbit heart slices reveals that cocaine, desipramine, chlorpromazine, and bretylium competitively inhibit amine uptake by the adrenergic neuronal membrane amine pump. Ouabain also inhibits, but by a noncompetitive mechanism. It is concluded that the membrane amine pump is linked energetically to the cardiac glycoside sensitive Na + -K + -dependent ATPase.

Summary New synthetic derivatives of natural cyclic nucleotides have been tested for their metabolic (blood glucose and plasma corticosterone) and cardiovascular (heart rate and blood pressure) effects in the rat. A clear cut specificity of the effects emerges from the comparison between the different series of substituted nucleotides (N 6 , 2′O-8-and 2-substitutions). A long lasting effect on plasma steroid levels has been demonstrated with the compound 6-(3′4′-dimethoxyphenyl-)ethyl-amino-3′,5′-PuMP + , at doses and times where there is no effect on the cardiovascular parameters or blood glucose levels.

Administration of 6-aminoindazole (6-AIN) and 5-aminoindazole (5-AIN) to rats depressed gastric acid secretion, both basal and carbachol-stimulated. 6-AIN proved to be more active than 5-AIN in decreasing the stimulated secretory process. The antisecretory activity of 6-AIN appears to be partially an antihistamine effect, since this compound antagonized the stimulatory action of betazole on isolated guinea pig auricle. The antisecretory activity of 6-AIN is probably associated with an antimuscarinic effect, since the molecule decreased carbachol-stimulated gastric acid secretion in rats and depressed neostigmine-stimulated motility of duodenum and colon in the anaesthetized cat. It also lessened the hypertonus of isolated guinea-pig trachea caused by pilocarpine. The antisecretory effects of 6-AIN also appear to be associated with myolytic activity, since it decreased the spontaneous motility of duodenum and colon in anaesthetized cats and the spontaneous myoactivity of isolated jejunum of the rabbit. It depressed the contractions of isolated guinea-pig ileum caused by histamine and decreased the spasmogenic effects of barium chloride on isolated guinea-pig gall bladder. These results suggest that 6-AIN probably depresses gastric acid secretion by interfering with both histamine and acetylcholine receptors and with other receptors involved in the secretory process.

The effect of fructose-1,6-diphosphate (FDP) on the recovery of post-arrest cardiac performance was assessed in isolated rabbit heart preparations subjected to cold ischemic cardioplegic arrest (CICA). Twenty-eight hearts were perfused with Krebs-Henseleit (KHBS) solution followed by 40 minutes of CICA. After CICA normothermic reperfusion with KHBS was restarted. The experimental preparations were divided in four groups of seven hearts each: one group served as control and the other three were perfused with KHBS supplemented with FDP (500 mg/l) given before CICA, after CICA or at both study points. Left ventricular end-diastolic pressure, left ventricular systolic pressure, dP/dt and perfusion pressure were measured at different pre- and post-arrest phases. Time analysis of recovery was also performed. The results demonstrated that FDP supplied prior to and after CICA: prevents the ventricular wall rigidity induced by the ischemic arrest, improves cardiac contractile force both in the basal condition and after cardioplegia, reduces the perfusion pressure, reduces the time to recovery of cardiac contractility. Our findings in the isolated rabbit heart are consistent with published data suggesting FDP may limit the impairment of cardiac dynamics induced by ischemia and improve the recovery after cardiac arrest.

LG 30435 is a new quarternary phenothiazine derivative with H1-antihistaminic and antimuscarinic properties. The ability of LG 30435 to prevent changes in respiratory mechanics, induced by different mediators and the immunological reaction, was monitored together with biological and radioimmunological determination of circulating thromboxane-A2 (TxA2) in anaesthetized guinea-pigs. LG 30435 dose-dependently reduces the bronchoconstriction and TxA2 generation caused by different stimuli such as histamine, acetylcholine, leukotriene C4 (LTC4) and PAF-acether. In addition i.v. and aerosol administration of LG 30435 causes a dose-dependent reduction of the increase in airway resistance and TxA2 generation induced by ovalbumin challenge in actively sensitized animals. LG 30435 infused at different concentrations through the isolated guinea-pig lungs inhibits the TxB2 generation caused by different anaphylactic mediators, but not by arachidonic acid. These data, which further substantiate the bronchodilator activity of LG 30435 against a variety of stimuli and demonstrate its protective properties on lung anaphylaxis, suggest that this compound has a potential therapeutic value in the treatment of asthma.

S-(+)-2-(4-Fluorophenyl)-alpha-methyl-5-benzoxazolacetic acid (flunoxaprofen, Priaxim is a new antiinflammatory compound, which in various biological systems interferes with the generation and release of arachidonic acid metabolites of the cyclo-oxygenase pathways without affecting the formation of 5- and 12-lipoxygenase products. Flunoxaprofen reduces the concentration of thromboxane (TX)B2 (ED50 = 35.4 mg/kg p.o.) and prostaglandin (PG)E2-like activity (ED50 = 39.9 mg/kg p.o.) in the inflammatory exudate of rats 8 h after implantation of sponges soaked with carrageenan, whereas the concentration of leukotriene (LT)B4 remains in the range of that of the untreated animals (3.1 ng/ml). Flunoxaprofen inhibits cell infiltration in the exudate and this suggests that LTB4 does not initiate cell recruitment but may represent a mechanism for amplifying the inflammatory response. Using human platelets challenged with collagen, flunoxaprofen only at higher concentration (10(-4) mol/l) reduces TXB2 formation without altering generation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid. This suggests a low capacity of flunoxaprofen of affecting platelet aggregation regulated by arachidonic acid metabolites. Flunoxaprofen prevents pulmonary changes due to secondary release of TXA2 in the guinea-pig. In fact this drug prevents changes due to immunological reaction and antagonizes bronchoconstriction due to exogenous administration of histamine and LTC4.(ABSTRACT TRUNCATED AT 250 WORDS)

Tiaramide hydrochloride (THC) is a benzothiazoline derivative with a remarkable antianaphylactic activity: in anaesthetized guinea-pig it shows protecting effects against histamine (H)- and bradykinin (Bk)-induced bronchoconstriction, preventing increase of lung resistance and decrease of dynamic compliance. At the same time THC inhibits formation of circulating thromboxane A2 brought about by H and Bk. THC is also able to antagonize the contractions induced by CaCl2 on isolated guinea-pig tracheal spirals and its mode of action seems to be of the competitive type. Furthermore THC abolishes the "tonic" phase of K+-induced contractions of guinea-pig taenia coli which are dependent on inward movement of calcium, whereas the "phasic" component of the contractions is left unaltered. THC is a very weak inhibitor of 3'-5' cyclic adenosine monophosphate phosphodiesterase which is affected only at very high dosage (10(-2) M). The calcium antagonistic activity of THC may explain both its bronchodilating and antianaphylactic properties.

In rats, the anti-inflammatory activity of parenteral S-adenosyl-L-methionine (SAMe) in carrageenin- and nystatin-induced oedemas and in carrageenin-induced pleurisy was tested. The capability of the drug to inhibit the production of PG-like material in sponge exudates and by peritoneal leukocytes during bacterial phagocytosis was also evaluated. Two of these experimental models were used to administer the compound by the oral route in order to see whether oral and injected SAMe had similar effects. The results obtained show that SAMe can exert anti-inflammatory activity by inhibiting the oedema and pleurisy in rats and PG-like material production in inflammatory exudates and in the phagocytosis process by leukocytes. The mechanism of action of SAMe is discussed.

Molecular Biology of Leukotriene Formation.- Fundamental Mass Spectrometry and Eicosanoids Research.- Quantitative Analysis of Eicosanoids by Gas Chromatography Mass-Spectrometry.- Formation and Mechanism of Action of Epoxyeicosatrienoic Acids.- Reactive Eicosanoid Intermediates and Transcellular Biosynthesis.- Metabolism of Sulfidopeptide Leukotrienes.- Lipoxins: Biosynthesis, Metabolism and Physiological Functions.- Leukotrienes in the Lung and Cardiovascular System.- Blood Platelets, Aspirin and Prevention of Vascular Disease.- Cardioprotective Effects of Prostacyclin Analogues.- New Pharmacological Agents Which Antagonize Leukotriene D4 and Platelet Activating Factor.- 9?, 11?-Prostaglandin F2: a New Prostanoid, That Inhibits Platelet Aggregation and Constricts Blood Vessels.- Stenosis and Vascular Damage as an Experimental Model of Arterial Thrombosis: a Role for Prostanoids.- Renal and Platelet Eicosanoids in Chronic Glomerular Disease.- Role of Leukotrienes in Experimental Gastric Ulceration.- Role of Leukotrienes in Inflammatory Bowel Disease.- Gastric Cytoprotection.- Gastric Mucosal Damage by Nonsteroidal Anti-Inflammatory Drugs.- Aspects of Eicosanoids in Inflammation.- Modulation of the Inflammatory Potential of the 5-Lipoxygenase Pathway by Alternative Fatty Acids and Cytokines.- Inhibitors of Leukotriene Action: Potential Use in Asthma, Inflammatory Bowel Disease, and Cutaneous Inflammation.- Novel 5-Lipoxygenase Inhibitors in Inflammation and Asthma.- Eicosanoids as Regulators of Eicosanoid Release in Macrophages:Impact for Exacerbation of Tissue Damage by Non-Steroidal Anti-Inflammatory Drugs.- Eicosanoid Regulation of Macrophage-Mediated Anti-Tumor Function.- Interactions Between Anti-Inflammatory Drugs and Cancer Chemotherapy.

In the isolated rabbit heart preparation we studied the action of defibrotide--a natural polydesoxyribonucleotide from mammalian lungs--on the ischemic myocardial injury and on concentration of prostaglandin-like material in the perfusate. Defibrotide counteracted the ischemic myocardial contracture and significantly improved the recovery of cardiac contractibility and normalization of the rhythm in the postischemic period. This effect seems to be correlated with the concentration of the prostaglandin-like material in the cardiac perfusate. A simultaneous infusion of indomethacin inhibited both the protective effect of defibrotide and the prostaglandin-like material release from the cardiac muscle.

The bronchodilating activity of mequitazine (MQ) (10-[3- quinuclidynilmethyl ]-phenothiazine) has been investigated in the guinea-pig using various spasmogens such as acetylcholine, histamine and leukotriene-C4 (LTC4). Mequitazine showed a potent protecting activity versus bronchoconstriction induced by the above agonists and was also able to prevent their capacity to trigger activation of arachidonic acid metabolism and preferential formation of TXA2. The results obtained with the "in vivo" experiments correlate well with those obtained "in vitro" using guinea-pig perfused lungs, where LTC4 and histamine stimulate TXA2 formation and release in the pulmonary effluent. MQ demonstrated its efficacy in protecting passively sensitized guinea-pigs from antigen challenge; this protection is accompanied by a substantial reduction of circulating TXA2. The bronchodilating and antiallergic activity of MQ is likely due to a direct control of histamine and muscarinic receptors and to a diminished bioamplification via eicosanoid activation. In addition, the capacity of MQ to counteract the "in vitro" and "in vivo" effects of LTC4 adds interest to its therapeutic potential.

A single daily administration of non-steroidal antiinflammatory drugs is widely recognized as the best dose regimen in chronic diseases such as degenerative osteoarthropathy, in inflammatory affections of the skeletal muscles, etc. Biomedical research has therefore developed drugs characterized either by a long half-life or available in a slow-release formulation. Isoxicam, piroxicam and benoxaprofen, which possess long half-lives, were compared with diclofenac sodium, indomethacin and ketoprofen, in their slow-release formulations, in terms of pharmacodynamics, pharmacokinetics and toxicity. Isoxicam, piroxicam and diclofenac showed excellent long lasting antiinflammatory properties: however the evidence showed that in cases of mild or severe renal pathology, drugs in their slow-release formulations are to be preferred.