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The present study investigated the effect of two single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, rs1544410 A/G and rs2228570 C/T, in modulating bone mineral density (BMD) and the response to treatment with bisphosphonates or strontium ranelate in postmenopausal osteoporosis (PMO). Four hundred eighteen postmenopausal women from Southern Italy treated with bisphosphonates or strontium ranelate for three years were enrolled and stratified according to their genotype. Changes in BMD were expressed as the delta t-score (Δt-score). Allelic frequencies for rs1544410 A/GSNP were 11.2% AA, 50.0% GA and 38.8% GG, for rs2228570 C/TSNP were 54.8% CC, 39.5% TC and 5.7% TT. TT carriers showed a lower t-score than TC and CC (both p &lt, 0.02) genotypes and were more responsive to the therapy when compared to both TC (p &lt, 0.02) and CC (p &lt, 0.05) carriers. Specifically, TT carriers receiving alendronate demonstrated a significant improvement of the Δt-score compared to TC and CC (both p &lt, 0.0001) carriers. After adjustment for confounders, the Δt-score showed evidence of a statistically significant positive association with TT in all treatments considered. Therapy response was independent of rs1544410 A/G SNP, instead, rs2228570 C/TSNP was associated with a better response to antiresorptive treatment, thus suggesting that the therapy for PMO should be personalized.

BACKGROUND: exercise-based Cardiac Rehabilitation Programme (CRP) is established as adjuvant therapy in heart failure (HF), nevertheless it is underutilized, especially in the elderly. While the functional and hemodynamic effects of CRP are well known, its underlying molecular mechanisms have not been fully clarified. The present study aims to evaluate the effects of a well-structured 4-week CRP in patients with stable HF from a molecular point of view. RESULTS: A prospective longitudinal observational study was conducted on patients consecutively admitted to cardiac rehabilitation. In fifty elderly HF patients with preserved ejection fraction (HFpEF), levels of sirtuin 1 (Sirt1) in peripheral blood mononuclear cells (PBMCs) and of its targets, the antioxidants catalase (Cat) and superoxide dismutase (SOD) in serum were measured before (Patients, P) and at the end of the CRP (Rehabilitated Patients, RP), showing a rise of their activities after rehabilitation. Endothelial cells (ECs) were conditioned with serum from P and RP, and oxidative stress was induced using hydrogen peroxide. An increase of Sirt1 and Cat activity was detected in RP-conditioned ECs in both the absence and presence of oxidative stress, together with a decrease of senescence, an effect not observed during Sirt1 and Cat inhibition. CONCLUSIONS: In addition to the improvement in functional and hemodynamic parameters, a supervised exercise-based CRP increases Sirt1 activity and stimulates a systemic antioxidant defence in elderly HFpEF patients. Moreover, CRP produces antioxidant and anti-senescent effects in human endothelial cells mediated, at least in part, by Sirt1 and its target Cat.

The synthesis and the pharmacological activity of a series of 1-aroyl derivatives of kynurenic acid methyl ester (4-oxo-quinolin-2-carboxy methyl (KYNA) esters), structurally related to NSAID indomethacin are described. The derivatives were screened in vivo for anti-inflammatory and analgesic activities. Most of the compounds exhibited good anti-inflammatory and analgesic activities. An automatic docking of the synthesized compounds was performed using X-ray structures of COX-1 and COX-2. Docking results are in good accordance with the experimental biological data.

Six series of N -acyl- N -phenyl ureas 1 – 6 of piperidine ( 1 ), and 2-ethyl- ( 2 ), 3-methyl- ( 3 ), 4-methyl- ( 4 ), 4-phenyl- ( 5 ), cis -2,6-dimethyl- ( 6 ) piperidine were synthesised and evaluated for their anti-inflammatory, anaesthetic, anti-pyretic properties. Some derivatives of series 1 and 5 were also assayed for anti-proliferative activity. Several compounds showed an anti-inflammatory activity comparable or slighty inferior to that of indomethacin in rats ( 1c , d , 2a , b , g , h , 3b , 4h , 5d , e ). Moreover, an appreciable anti-inflammatory activity was also found in 2c , e , 3e , f , g , 4g , 5a , b , c , f , h , and 6a , b , d . All the compounds were devoid of anti-pyretic activity and only a few of them exhibited a low level of infiltration anaesthesia in mice. Compound 5a showed a broad spectrum anti-cancer activity (at low micromolar concentrations), particulary significant against leukemia subpanel.

The synthesis of a group of 2-phenylimidazo[1,2-b]pyridazine-3-acetic esters and acids is described. The structures of the new compounds are supported by 1H-NMR spectra. These compounds were tested in vivo for their anti-inflammatory, analgesic and ulcerogenic activity. All new compounds showed remarkable anti-inflammatory action in the carrageenan rat paw oedema (one third of that for indomethacin) but no significant analgesic activity in the acetic acid writhing test together with negligible ulcerogenic action, and were also found to be lacking inhibitory activity on cyclooxygenase in vitro.

4,6-diaryl and 4,6-aryl-indolyl substituted 3-cyano-2-aminopyridines were synthesized and submitted to evaluation for their anti-inflammatory, analgesic and antipyretic activity. The electronegativity of the substituents and their displacement on the 4- or 6-aryl ring of the 4,6-diaryl-3-cyano-2-aminopyridine nucleus ( 3a – q ) influenced the anti-inflammatory activity which was higher in the presence of electron-realising groups. The introduction of the indol-3-yl substituent in the 4-position of the 3-cyano-2-aminopyridine nucleus ( 6a – x ) increased the anti-inflammatory and analgesic power, but there was no evidence of the relationship among the electronic characteristic of the substituents, their displacement on the 6-phenyl ring and the activity. Conversely, the displacement of the 2-hydroxyphenyl group in the 4-position ( 4a – e ) and of the indol-3-yl group in the 6-position ( 8h – w ) decreased the anti-inflammatory activity. All derivatives did not show any significative antipyretic activity.

A series of 2-phenylimidazo[1,2-a]pyridine-3-carboxylic esters, acids, and amides were synthesized and pharmacologically tested in order to evaluate their antiinflammatory and analgesic activity and their ulcerogenic action on the gastro-intestinal tract. The most active member of this series of compounds was found to be 6-methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylic acid (5c).

Some aliphatic and aromatic esters 2a–l were prepared starting from 5-aryl-1,2,4-triazoline-3-thiones bearing a 2-hydroxyethyl chain in position 2. The title compounds were evaluated for antipyretic and anti-inflammatory activities. Nearly all derivatives and in particular 2f , 2h , 2k exhibited antiphlogistic properties but were lacking in antipyretic activity.

AB Purpose: Moderate aerobic exercise reduces oxidative stress, whereas intense physical activity may produce the opposite result. At present, the effects of different exercise loads on oxidative stress markers and the response of human cells to different exercise volumes have not been fully elucidated. Methods: Human (Eahy-926) endothelial cells (EC), exposed or not exposed to oxidative stress, were conditioned with sera from two groups of triathletes practicing at different workloads. Results: Although no differences in functional and hemodynamic variables were observed between the two groups of triathletes, significant changes in some markers for oxidative stress were found in their sera. Thiobarbituric acid reactive substances and superoxide dismutase activity were similar, but triathletes practicing the sport at lower volume (T1) had higher serum nitric oxide and lower catalase activity than triathletes performing the training at greater load (T2). The EC conditioned with serum from T1 (T1-EC) showed higher survival and proliferation rates and lower senescence levels than the EC supplemented with T2 (T2-EC) serum both before and after oxidative stress induction. These effects depended on catalase as demonstrated via enzyme activity inhibition using 3-amino-1,2,4-triazole. After oxidative stress induction, Sirt1 activity, a regulator of the oxidative stress response, was significantly increased in the T1-EC but not in the T2-EC. Moreover, the T1-EC required less catalase activity than the T2-EC to counteract an equal amount of oxidative stress after H2O2 administration. Conclusion: This study demonstrates that the beneficial effects of aerobic exercise are eliminated when the training is performed at a greater workload. Moreover, we suggest an oxidative stress marker, serum catalase activity, as a valid tool to use in the supervision of changes to exercise volume.

Purpose: Exercise training is a nonpharmacological intervention that improves cardiovascular function and enhances endothelial homeostasis in patients with cardiovascular diseases. However, the amount of benefit achieved varies widely depending on the type and duration of exercise. Moreover, data about the long-term effects of physical activity are scarce. Methods: In this study, endothelial cells, exposed or not to oxidative stress, were conditioned with sera from athletes regularly participating in sports classified as �aerobic� (triathlon), �mixed aerobic�anaerobic� (soccer), and �anaerobic� (sprint running). Results: Functional and hemodynamic variables did not differ between groups of athletes, whereas there were dramatic changes in serum markers for oxidative stress. Lipid peroxidation assessed by the thiobarbituric acid reactive substances assay and catalase activity were the lowest and nitric oxide availability was the highest in sera of triathletes. Endothelial cells cultured in serum from triathletes (T-endothelial cells) had the highest survival, evaluated by viability assay, BrdU incorporation, and senescence-associated s galactosidase assays, and preserved the endothelial appearance before and after stress in contrast to the cells grown in sera from the other athletes. T-endothelial cells also had the highest catalase messenger RNA expression and, after stress, the highest catalase activity of all the endothelial cells. Moreover, poststress activity of Sirt1, a NAD+-dependent deacetylase involved in cellular stress resistance and a key regulator of longevity, was significantly increased in T-endothelial cells. Conclusions: Different types of exercise training induced different molecular effects in terms of survival, morphology, and antioxidant system efficiency. The in vitro technique used herein may help to shed light on the molecular basis of effects of long-term physical activity in humans.

Synthesis and pharmacological activity of a series of N-aroyl derivatives (I) of kynurenic acid methyl esters, structurally related to NSAID indomethacin are described.

Reaction of methyl 4-methoxy-2-dimethylaminomethylene-3-oxobutanoate with arylhydrazines gave methyl 1-aryl-5-(methoxymethyl)-1H-pyrazole-4-carboxylates 1 in high yields. Esters 1 were hydrolyzed to the relative carboxylic acids, which were converted by heating to 1-aryl-5-(methoxymethyl)-1H-pyrazoles 3 in good yields. Reaction of 3 with hydrobromic acid afforded the intermediate 1-aryl-5-(bromomethyl)-1H-pyrazoles, which were converted with potassium cyanide to 1-aryl-1H-pyrazole-5- acetonitriles, whose hydrolysis gave the required 1-aryl-1H-pyrazole-5-acetic acids. Some acids 5 showed a strong antiinflammatory and analgesic activity in rats and mice, respectively, as well as moderate antipyretic and in vito platelet antiaggregating effects.

The synthesis of 5-[[omega-(dialkylamino)alkoxy]methylene]-1,3,3-trimethyl-2- oxabicyclo[2.2.2]octan-6-ones by reaction of (+)-5-(hydroxymethylene)-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan- 6-one with a series of omega-(chloroalkyl)dialkylamines in the presence of potassium carbonate is described. Some compounds showed strong hypotensive, local anesthetic and antiarrhythmic activity in rats and mice, as well as moderate analgesic, antipyretic and in vitro platelet antiaggregating activity.

The synthesis in excellent yields of 2,3-dihydro-6-mercapto-1,3,5-triphenyl-2-thioxo-4(3H)-pyrimidinone 3 and 5-ethoxycarbonyl-2,3-dihydro-6-mercapto-1,3-diphenyl-2-thioxo-4(3H )- pyrimidinone 4 by reaction of methyl phenylacetate or diethyl malonate, respectively, with phenyl isothiocyanate (3 molar equivalents) and sodium hydride (2 molar equivalents) in DMF solution is described. Acylation of 3 and 4 with acyl chlorides gave, generally in satisfactory yields, 6-acylthio derivatives 13 and 14. Some of the above compounds showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid, as well as remarkable antiinflammatory, antiarrhythmic, local anesthetic and antihyperlipidemic activities in rats and in mice. Weak anticonvulsant and hypoglycemic activities were also detected.

The synthesis of some O-(2-dialkylaminoethyl)oximes of 5-[(4-methoxy- or 4-methylthiophenyl)methylene]-1,3,3-trimethyl-2-oxabicyclo[2.2.2] octan-6-ones 5 by reaction of the corresponding oximes as sodium salts with the appropriate 2-chloroethyldialkylamine in dry ethanol solution is described. Some aminoethers 5 showed appreciable hypotensive and antiarrhythmic activities in rats, as well as a weak platelet antiaggregating activity in vitro and a moderate infiltration anesthesia in mice.

The synthesis of novel 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles 4a-f, starting from N-phenyl-3,4-dihydro-1(2H)-oxonaphthalene-2-carbothioamide and the proper arylhydrazines, is described. Title compounds were evaluated for antiinflammatory, analgesic, antipyretic, antiarrhythmic, hypotensive, local anaesthetic and platelet antiaggregating activities; some of them showed an appreciable antiarrhythmic activity in rats and a good level of infiltration anaesthesia in mice.

The title compounds were synthesized by cyclizing 3-dimethylaminomethylene-4-chromanone with creatine to give the acid 2 that was successively converted into the corresponding amides 3a-f via diphenylphosphorylazide and the relevant amines. The free acid 2 and some of 3a-f showed antiinflammatory, hypotensive and antiarrhythmic properties.

The synthesis of some N,N-disubstituted 1-amino-2-phenyl-3H,12H-naphtho[1,2-b]pyrano[2,3-d]pyran-3-ones 4, by reaction of phenylchloroketene with a series of N,N-disubstituted 3-aminomethylene-2,3-dihydro-4H-naphtho[1,2-b]pyran-4-ones, followed by dehydrochlorination in situ of the primary adducts with DBN, is described. Some compounds 4 showed antiarrhythmic and analgesic activities.

A series of 2-aryl-6-methyl-3-phenylamino-6,7-dihydropyrano[4,3-c]pyrazol-4(2H )-ones were prepared and tested for antiinflammatory, analgesic, antipyretic, antiarrhythmic, antihypertensive and platelet antiaggregating activities. All of them showed an appreciable level of analgesic activity in mice.

The synthesis of 6-thiosubstituted 5-ethoxycarbonyl-1,3-diphenyl-2-thioxo-2,3-dihydropyrimidin- 4(1H)-ones 3, and of 6-substituted 5-hydroxy-1,3-diphenyl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones 5 and their esters 6 is described. These derivatives were prepared in order to evaluate the influence on the pharmacological profile of alkyl substituents bearing polar/hydrophilic functionalities at an enethiol substructure as in compounds 3 or to assess the effects arising from the incorporation of the sulfur atom in a thiophene moiety as in thienopyrimidinones 5 and 6 in comparison with a series of 5-substituted 6-acylthio-1,3-diphenyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones 1c,d, previously described. Preliminary screenings suggest that all tested compounds maintained or even increased the local anesthetic activity, but failed in the platelet antiaggregating activity; on the other hand, antiarrhythmic and antiinflammatory activity was preserved in some esters 6.

A series of angelicin heteroanalogues, in which the furan was replaced by thiophene or a 1-substituted pyrazole moiety, was synthesised in order to obtain potential therapeutic agents with antiproliferative and/or other biological activities. In general, the antiproliferative activity of the new thioangelicin, tested in different biological substrates, appeared to be higher than that of the angelicin, the natural parent compound, but lower than that of 8-MOP, the furocoumarin ordinarily used in PUVA therapy and photopheresis. Thioangelicin 6 induced strong inhibition of T2 bacteriophage infectivity and was able to significantly repress the DNA synthesis in Ehrlich ascites cells and the clonal growth in HeLa cells. The pyrazolocoumarins did not show any noticeable effect upon UVA irradiation in all the biological systems considered. All the new angelicin heteroanalogues appeared to be free of the known phototoxicity of furocoumarins on the skin. The pyrazolocoumarins have also been tested as anti-inflammatory, analgesic, antipyretic, local anaesthetic, anti-arrhythmic and platelet anti-aggregating agents by standard procedures. In this class of derivatives, 10a showed good anti-inflammatory and antipyretic properties, while 9a and 11a showed significant local anaesthetic activity.

A series of 1,3,4-thiadiazol-2(3H)-ones (2a–j) with a nicotinoyl/isonicotinoyl group in position 3 and an aroylamino substituent in position 5 of the ring was prepared and evaluated for antipyretic and anti-inflammatory activities. All the title compounds and in particular 2e, 2i and 2j exhibited anti-inflammatory activity and were devoid of antipyretic properties.

A series of N -methyl- N -pyrimidin-2-yl glycines 2a–e , having the pyrimidine ring fused with a cyclohexane [ N -methyl- N -(5,6,7,8-tetrahydroquinazolin-2-yl)glycine], cyclohexene [ N -methyl- N -(5,6-dihydroquinazolin-2-yl)glycine], 1,2,3,4-tetrahydronaphthalene [ N -methyl- N -(5,6-dihydrobenzo[e]quinazolin-2-yl)glycine], benzopyrane [ N -methyl- N -(5-phenyl-5 H -[1]benzopyrano[4,3- d ]pyrimidin-2-yl)glycine] and benzothiopyrane [ N -methyl- N -(5 H -[1]benzothiopyrano[4,3- d ]pyrimidin-2-yl)glycine] ring, was prepared and tested for antiinflammatory activity. With the same purpose a number of N -5 H -[1]benzopyrano[4,3- d ]pyrimidin-2-yl substituted amino acids 3a–e , having a different chain length and branching were also synthesized and tested. All the described products 2 and 3 showed an appreciable antiphlogistic activity, particularly 2b and 2c .

The synthesis of a series of 1,2,4-triazolo[4,3-a]quinoline derivatives is described; their structures were assigned by 1H NMR and analytical data. The new compounds were tested in vivo for their antiinflammatory and analgesic activities, as well as for their ulcerogenic action. Some of the tested triazoles showed an analgesic activity in the acetic acid writhing test and antiinflammatory properties on carrageenan paw edema assay.

3-Cyano-4-(R,R′-aryl)-6(2-hydroxyphenyl)-2-(1H)pyridones 2a–o and 3-cyano-4-(R-R′-aryl)-6-(2-hydroxyphenyl)-2-aminopyridines were synthesized which showed anti-inflammatory and analgesic activity. Electron withdrawing substituents in 2′ or 4′ position on 4-aryl group of compounds 2 increased the anti-inflammatory activity, while their displacement in the 3′ position produced an increase of analgesic activity and the appearance of an edematous reaction. All compounds showed low antipyretic and antimicrobial activity. The compounds 2b, 2d, 2i, 2m and 2o did not show any interesting activity in the β-adrenolytic, antihypertensive and heart frequency tests.

Two series of N-[5-oxo-4-(arylsulfonyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl]-amides were synthesized and tested in vivo for their analgesic and anti-inflammatory activities. All the new compounds possess good antalgic action in the acetic acid writhing test and some terms of the series showed also fair anti-inflammatory activity in the carrageenan rat paw edema test. Ulcerogenic and irritative action on the gastrointestinal mucose, in comparison with indomethacin is low.

The aim of this study was to test the effects of age and chronic exercise training on antioxidant and heat shock protein (Hsp) expression by comparing the hearts of young (Y), sedentary old (SO) and trained old (TO) rats. In SO rats, there were: (a) changes in myocardial structure and function; (b) increased malondialdehyde levels; (c) no changes in superoxide-dismutase (SOD) enzymes; (d) reduced Hsp70 expression; and (e) increased Hsp27 expression. In TO rats, SOD enzymes and Hsp70 expression were increased and Hsp27 was further increased. Malondialdehyde level did not differ between TO and SO rats, which shows that chronic exercise did not affect the peroxidation index. In summary, by increasing Hsp27 and Hs70 levels, prolonged exercise partially counterbalanced the heart age-related effects in the antioxidant system without altering peroxidation levels. These findings suggest that the beneficial effects on aged-related cardiovascular changes could be connected to the "anti-oxidant" effects of prolonged exercise training.

Three series of N-acyl and N-cyclohexyl- or N-methyl or N-phenyl-thioureas of 4-substituted (methyl, phenyl, 2-pyridyl)piperazines (4-12) were synthesised according to a highly convergent one-pot procedure and tested in vivo (local anaesthetic, anti-hyperlipoproteinemic, analgesic, anti-inflammatory, antiarrythmic activities) and in vitro (antiaggregating and, for some selected derivatives, antiproliferative activities) experiments. All the test compounds showed local anaesthesia in particular 4Ar(4), 5Ar(4), 12Ar(3) (after 5 min) and 5Ar(2), 5Ar(3), 9Ar(4) (after 30 min) were equipotent to lidocaine. In lowering triglyceride levels, compounds 6Ar(4) and 7Ar(3) were more active than nicotinic acid, whereas 7Ar(4) and 11Ar(4) were approximately equipotent. As concerns analgesic activity, 5Ar(2) and 5Ar(4) were as active as indomethacin. Appreciable anti-inflammatory activity was found in 8Ar(1), 5Ar(2) and 11Ar(2), but inferior to that of indomethacin. High levels of antiarrythmic activity, comparable with that of quinidine, were found in derivatives 4Ar(2) and 10Ar(1). Compounds 4Ar(2) and 8Ar(2), assayed in antitumor in vitro screening system at National Cancer Institute (NCI), showed significant antiproliferative activity against ACHN cell line (GI50: 0.13 microM) and NCI-H226 cell line (GI50: 1.03 microM), respectively.

Gastroesophageal acid reflux (GER) is a common disorder associated with the exacerbation of asthma. In this study we investigated the effects on the airways of intraoesophageal HCl instillation in the rabbit and the role of tachykinins in these effects. In anaesthetized New Zealand rabbits bronchopulmonary functions [total lung resistance (R(L)) and dynamic compliance (C(dyn))] were calculated before and after HCl intraoesophageal instillation. Infusion of HCl induced a significant bronchoconstriction (P0.05) in the terms of R(L) and C(dyn) changes, that were increased by phosphoramidon pre-treatment and reduced by capsaicin pre-treatment. Moreover, a pre-treatment with SR 48968, a tachykinin NK2 receptor antagonist, or SR 140333, a NK1 receptor antagonist, significantly inhibited the bronchoconstriction induced by intraoesophageal HCl infusion in terms of R(L) and C(dyn)changes. Finally, the HCl induced bronchoconstriction was unaffected by SR 142801, a tachykinin NK3 receptor antagonist. In conclusion these results suggest that bronchoconstriction induced by intraoesophageal HCl infusion is mainly dependent on the release of tachykinins and that both NK1 and NK2 tachykinin receptors are involved.

A series of 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles was synthesized and tested for antiarrhythmic, local anaesthetic and analgesic activity. The title compounds showed a good antinociceptive activity.

The synthesis of a series of 1,2,4-triazolo[4,3-a]quinoline derivatives is described; their structures were assigned by 1H NMR and analytical data. The new compounds were tested in vivo for their antiinflammatory and analgesic activities, as well as for their ulcerogenic action. Some of the tested triazoles showed an analgesic activity in the acetic acid writhing test and antiinflammatory properties on carrageenan paw edema assay.

Two series of 3-arylsulphonyl-5-arylamino-1,3,4-thiadiazol-2(3H)ones 2 with potential anti-inflammatory and analgesic activity were prepared and tested. Pharmacological results revealed that all the title compounds, endowed with an arylsulphonyl side chain, possess good antalgic activity and fair anti-inflammatory properties. The analgesic profile of the two series, evaluated by the acetic acid writhing test, showed that compouds 2c, 2f and 2h, in particular, were the most active. Structure-activity relation- ships are briefly discussed. # 2001 Elsevier Science Ltd. All rights reserved.

Seventeen (un)substituted N-[4-(propyl)cyclohexyl]-amides (6a–h, 7a–h and 8) were synthesized and tested as anti-inflammatory and analgesic agents. The substituents on the aromatic ring were chosen in order to study the influence of electron-withdrawing or electron-donating residues, that change the electronic density on the aromatic moiety. The pharmacological results allow drawing some preliminary considerations on structure–activity relationships.

A novel series of O-[2-hydroxy-3-(dialkylamino)propyl]ethers of (+)-camphor oxime was prepared and tested for its cardiovascular, analgesic and anti-inflammatory properties. No significant anti-inflammatory and hypotensive activities were displayed by any of the compounds, whereas several of them are reasonably active as antiarrhythmic and analgesic agents.

A series of indazoloxypropanolamines 7 and 8, pindolol isosteres, were synthesized to extend the structure activity relationship (SAR) which was observed in an earlier series of related derivatives. Compounds 7, characterized by methyl substitution on the N-1 indazole nucleus, generally exhibited significant antiarrhythmic, local anaesthetic and analgesic activities. The preliminary radioligand binding assay highlighted, in compounds 7, an interesting beta 1-affinity which can be well correlated to their antiarrhyhtmic activity. Analogues 8 characterized by a phenyl group on the N-1 indazole nucleus, were generally less active as antiarrhyhtmic agents but generally interesting as local anaesthetics. Due to the importance of the indazole moiety as a carrier of antiphlogistic activity, the two classes of derivatives 7 and 8 were evaluated for their NSAID behaviour. Once again, compounds 7 resulted having more interesting analgesic and antipyretic effects than analogues 8.

A novel series of O-[2-hydroxy-3-(dialkylamino)propyl]ethers of (+)-camphor oxime was prepared and tested for its cardiovascular, analgesic and anti-inflammatory properties. No significant anti-inflammatory and hypotensive activities were displayed by any of the compounds, whereas several of them are reasonably active as antiarrhythmic and analgesic agents.

Data concerning patients undergoing antibiotic treatment for upper (URTI) or lower (LRTI) respiratory tract infections were collected from 23 General Practitioners (GPs) in the Campania Region of Italy from November 15, 1997 to March 15, 1998. The objectives of the study were: a) to assess the occurrence of URTIs and LRTIs; b) to document the factors that influence GPs' choice of therapy; c) to correlate antibiotic choice with duration and outcome of treatment; d) to assess the incidence of unwanted effects. 2198 questionnaires were collected. Patients were +/-43.9 of age. URTIs were diagnosed in 65.4% and 34.6% LRTIs. The mean duration of antibiotic treatment was 4.5 days in URTIs and 5.6 days in LRTIs. The choice of antibiotic treatment was influenced by clinical assessment of infections (67.1%). The most commonly used antibiotic categories in URTIs were macrolides (39.3%), penicillins (27.4%) and cephalosporins (23.8%) whereas for LRTIs mainly cephalosporins (63.8%), penicillins (9.2%) and fluoroquinolones (7.4%) were used. Adverse events were experienced by 3.9% of patients.

A series of substituted 3-(arylamino)-4,5-dihydro-2H-benz[g]indazol-2-yl acetamides was synthesized and tested in comparison with former analogues. The title compounds showed only weak antiarrhythmic properties but good anti-inflammatory and antinociceptive activity, particularly evident in the morpholino derivative.