Presence of peripheral arthritis and male sex predicting continuation of anti-tumor necrosis factor therapy in ankylosing spondylitis: an observational prospective cohort study from the South Swedish Arthritis Treatment Group Register.

OBJECTIVE: To examine clinical characteristics as possible predictors of long-term treatment continuation with adalimumab, etanercept, and infliximab in ankylosing spondylitis (AS) patients who had never taken biologics treated in clinical practice. METHODS: Patients in southern Sweden with active AS starting biologic therapy for the first time between October 1999 and December 2008 (n = 243, 75% men) were included in a structured clinical followup over 2 years. Patients with clinical spondylitis had not responded to at least 2 nonsteroidal antiinflammatory drugs, whereas patients who also had peripheral arthritis (n = 121) had additionally failed at least 1 conventional disease-modifying antirheumatic drug (DMARD) treatment course. The mean ± SD age at inclusion was 43 ± 12 years, with a mean ± SD disease duration prior to treatment of 16 ± 12 years. RESULTS: The 2-year drug continuation rate was 74%. Male sex (hazard ratio [HR] of premature discontinuation 0.36 [95% confidence interval (95% CI) 0.19-0.68]) and the presence of peripheral arthritis (HR 0.49 [95% CI 0.27-0.88]) were found to be significant predictors of better drug survival. Furthermore, a trend was seen for more favorable drug continuation on treatment with etanercept as compared with infliximab (HR 0.50 [95% CI 0.25-1.04], P = 0.062), whereas no differences were found comparing the 3 anti-tumor necrosis factor agents in other ways. Higher baseline C-reactive protein level (HR 0.99 [95% CI 0.97-1.00], P = 0.12) and concomitant treatment with nonbiologic DMARDs (HR 0.61 [95% CI 0.34-1.10], P = 0.10) also showed trends to entail better drug adherence. CONCLUSION: AS patients in this study have an excellent 2-year drug survival rate of 74%. Significant predictors for treatment continuation in this study were male sex and the presence of peripheral arthritis.

Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register.

OBJECTIVES: To study treatment response rates of RA patients undergoing second- and third-line anti-TNF therapy and to identify baseline predictors of response to second-line treatment. METHODS: RA patients monitored in a prospective, observational study, having switched anti-TNF therapy once (first-time switchers, n = 337) or twice (second-time switchers, n = 36)--i.e. following failures with one antibody- and one receptor-type agent--between March 1999 and December 2006, were studied. Treatment responses at 3 months were assessed by the ACR and European League Against Rheumatism (EULAR) response criteria. Predictive potentials for response to second-line treatment of demographics, baseline disease activity measures, disease and treatment characteristics were analysed using logistic regression. RESULTS: ACR20 response was met by 51% of first-time and 35% of second-time switchers. Corresponding ACR50 rates were 27 and 18%; EULAR overall rates (EULAR good or moderate response) 71 and 58%; EULAR good rates 25 and 9% and 28-joint disease activity score (DAS28) remission rates 16 and 6%. Identified baseline predictors of response to second-line treatment were lower age and HAQ scores, elevated DAS28 values and having ceased the former anti-TNF treatment due to adverse events rather than inefficacy. No variable was predictive for all examined response criteria. CONCLUSIONS: Response rates of first-time anti-TNF switchers are somewhat below those of anti-TNF naïve RA patients, while the markedly inferior response rates of second-time switchers suggest other therapeutic options to be considered in this situation. Identified baseline predictors of response may be useful indicators to second-line anti-TNF therapy, but vary depending on the response criteria set studied.

RPR 106541, a novel, airways-selective glucocorticoid: effects against antigen-induced CD4+ T lymphocyte accumulation and cytokine gene expression in the Brown Norway rat lung.

1. The effects of a novel 17-thiosteroid, RPR 106541, were investigated in a rat model of allergic airway inflammation. 2. In sensitized Brown Norway rats, challenge with inhaled antigen (ovalbumin) caused an influx of eosinophils and neutrophils into the lung tissue and airway lumen. In the lung tissue there was also an accumulation of CD4+ T lymphocytes and increased expression of mRNA for interleukin-4 (IL-4) and IL-5, but not interferon-gamma (IFN-gamma). These findings are consistent with an eosinophilia orchestrated by activated Th2-type cells. 3. RPR 106541 (10-300 microg kg[-1]), administered by intratracheal instillation into the airways 24 h and 1 h before antigen challenge, dose-dependently inhibited cell influx into the airway lumen. RPR 106541 (100 microg kg[-1]) caused a significant (P<0.01) (98%) inhibition of eosinophil influx and a significant (P<0.01) (100%) inhibition of neutrophil influx. RPR 106541 was approximately 7 times and 4 times more potent than budesonide and fluticasone propionate, respectively. 4. When tested at a single dose (300 microg kg[-1]), RPR 106541 and fluticasone each caused a significant (P<0.01) (100%) inhibition of CD4+ T cell accumulation in lung tissue. Budesonide (300 microg kg[-1]) had no significant effect. RPR 106541 and fluticasone (300 microg kg[-1]), but not budesonide (300 microg kg[-1]), significantly (P<0.05) inhibited the expression within lung tissue of mRNA for IL-4. RPR 106541 (300 microg kg[-1]) also significantly (P<0.05) inhibited expression of mRNA for IL-5. 5. The high topical potency of RPR 106541 in this model, which mimics important aspects of airway inflammation in human allergic asthmatics, suggests that this glucocorticoid may be useful in the treatment of bronchial asthma.

IFN-gamma production from human Th1 cells is controlled by Raf kinase.

Raf kinase is an important intracellular mediator in T cell signalling and may be crucial for the proliferation of this inflammatory cell. In order to elucidate its effect on cytokine production by human T cells in response to T cell receptor activation, experiments were carried out on human T cell clones using antisense (AS) oligodeoxynucleotides (ODN) to inhibit the expression of Raf kinase. AS ODN to Raf were shown to have a significant effect on a human Th1-like T cell clone, inhibiting antiCD3-induced IFN-gamma secretion by 76%, whereas no inhibitory effect was observed on IL-5 or IL-4 production by a Th2-like clone. IL-2 secretion from both clones was also not affected by the Raf AS ODN. In all cases, a reduction in Raf kinase within the cell was demonstrated by Western blot. Our results clearly demonstrate the importance of Raf kinase in the production of IFN-gamma from Th1 cells, but also show the lack of effect of this intracellular mediator on cytokine (IL-5, IL-4) release from Th2 cells.

Anti-inflammatory 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma.

The synthesis and anti-inflammatory potencies of a new class of 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compounds from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17beta-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compounds with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17beta-thioalkyl-16alpha,17alpha-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.

The role of capsaicin-sensitive C-fibre afferent nerves in the cough reflex.

While airway rapidly adapting receptors can mediate the cough reflex, much evidence suggests that bronchial C-fibre receptors are also involved in guinea-pigs and man. In man local and systemic C-fibre stimulants have a potent tussive action, which is blocked by low doses of local anaesthetics which leave the reflex bronchoconstriction intact. In guinea-pigs destruction of airway C-fibre receptors by large doses of capsaicin abolishes the cough reflex due to capsaicin and citric acid. Thus there may be subpopulations of airway C-fibres responsible for the different reflexes such as apnoea, cough and bronchoconstriction. The evidence for the role of C-fibre receptors in cough is described and discussed.

Effects of RP 73401, a novel, potent and selective phosphodiesterase type 4 inhibitor, on contractility of human, isolated bronchial muscle.

1. The aim of this study was to investigate the smooth muscle relaxant effects of the novel, selective phosphodiesterase (PDE) type 4 inhibitor, RP 73401 in comparison with the classical PDE 4 inhibitor, rolipram, the non-selective PDE inhibitor, theophylline and the beta-adrenoceptor agonist, isoprenaline on the human, isolated bronchus. 2. At resting tone, the rank order of potency (pD2) for the relaxants was RP 73401 > or = rolipram > or = isoprenaline >> theophylline. In terms of maximum relaxation produced (Emax) the PDE 4-selective inhibitors were similar, but the maximal effects (70-75% of theophylline, 3 mM) were lower than that observed with isoprenaline (98% of theophylline, 3 mM) or theophylline itself (100%). 3. On the human isolated bronchus pre-contracted with acetylcholine (ACh, 0.1 or 1.0 mM), the rank order of potency remained the same. The maximal responses to RP 73401 and rolipram were however markedly reduced (Emax 39.9-46.6%) compared with isoprenaline (Emax 79-85%). 4. In tissues pre-contracted with ACh (0.1 mM), RP 73401 and rolipram (10(-9)-10(-7) M) significantly and concentration-dependently increased tissue sensitivity to isoprenaline. RP 73401 and rolipram were similar in potency. Both selective PDE 4 inhibitors also significantly increased the maximal relaxant effects of isoprenaline. These effects were not observed with the PDE 3 inhibitor, siguazodan. 5. In terms of retention by tissues (an index of duration of action), the onset of action of RP 73401 (2.11 +/- 0.53 min) and rolipram (1.70 +/- 0.45 min) was significantly slower than that of isoprenaline (0.33 +/- 0.06 min) or theophylline (1.17 +/- 0.25 min). The retention of RP 73401 (89.0 +/- 21.9 min) on the human isolated bronchial tissues after washing was however dramatically longer than that of rolipram (18.3 +/- 4.5 min), theophylline (3.43 +/- 0.58 min) or isoprenaline (2.81 +/- 0.31 min). 6. These data indicate that RP 73401 is a potent and long acting relaxant of human bronchial muscle in vitro. RP 73401 is more potent than the classical PDE 4-selective inhibitor rolipram and the non-selective PDE inhibitor theophylline and is retained in bronchial tissue for a much longer period of time.

Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with a 'low-affinity' phosphodiesterase 4 conformer.

1. We have investigated the inhibitory effects of RP 73401 (piclamilast) and rolipram against human monocyte cyclic AMP-specific phosphodiesterase (PDE4) in relation to their effects on prostaglandin (PG)E2-induced cyclic AMP accumulation and lipopolysaccharide (LPS)-induced TNF alpha production and TNF alpha mRNA expression. 2. PDE4 was found to be the predominant PDE isoenzyme in the cytosolic fraction of human monocytes. Cyclic GMP-inhibited PDE (PDE3) was also detected in the cytosolic and particulate fractions. Reverse transcription polymerase chain reaction (RT-PCR) of human monocyte poly (A+) mRNA revealed amplified products corresponding to PDE4 subtypes A and B of which the former was most highly expressed. A faint band corresponding in size to PDE4D was also observed. 3. RP 73401 was a potent inhibitor of cytosolic PDE4 (IC50: 1.5 +/- 0.6 nM, n = 3). (+/-)-Rolipram (IC50: 313 +/- 6.7 nM, n = 3) was at least 200 fold less potent than RP 73401. R-(-)-rolipram was approximately 3 fold more potent than S-(+)-rolipram against cytosolic PDE4. 4. RP 73401 (IC50: 9.2 +/- 2.1 nM, n = 6) was over 50 fold more potent than (+/-)-rolipram (IC50: 503 +/- 134 nM, n = 6) ) in potentiating PGE2-induced cyclic AMP accumulation. R-(-)-rolipram (IC50: 289 +/- 121 nM, n = 5) was 4.7 fold more potent than its S-(+)-enantiomer (IC50: 1356 +/- 314 nM, n = 5). A strong and highly-significant, linear correlation (r = 0.95, P < 0.01, n = 13) was observed between the inhibitory potencies of a range of structurally distinct PDE4 inhibitors against monocyte PDE4 and their ED50 values in enhancing monocyte cyclic AMP accumulation. A poorer, though still significant, linear correlation (r = 0.67, P < 0.01, n = 13) was observed between the potencies of the same compounds in potentiating PGE2-induced monocyte cyclic AMP accumulation and their abilities to displace [3H]-rolipram binding to brain membranes. 5. RP 73401 (IC50: 6.9 +/- 3.3 nM, n = 5) was 71 fold more potent than (+/-)-rolipram (IC50: 490 +/- 260 nM, n = 4) in inhibiting LPS-induced TNF alpha release from monocytes. R-(-)-rolipram (IC50: 397 +/- 178 nM, n = 3) was 5.2-fold more potent than its S-(+)- enantiomer (IC50: 2067 +/- 659 nM, n = 3). As with cyclic AMP, accumulation a closer, linear correlation existed between the potency of structurally distinct compounds in suppressing TNF alpha with PDE4 inhibition (r = 0.93, P < 0.01, n = 13) than with displacement of [3H]-rolipram binding (r = 0.65, P < 0.01, n = 13). 6. RP 73401 (IC50: 2 nM) was 180 fold more potent than rolipram (IC50: 360 nM) in suppressing LPS (10 ng ml-1)-induced TNF alpha mRNA. 7. The results demonstrate that RP 73401 is a very potent inhibitor of TNF alpha release from human monocytes suggesting that it may have therapeutic potential in the many pathological conditions associated with over-production of this pro-inflammatory cytokine. Furthermore, PDE inhibitor actions on functional responses are better correlated with inhibition of PDE4 catalytic activity than displacement of [3H]-rolipram from its high-affinity binding site, suggesting that the native PDE4 in human monocytes exists predominantly in a 'low-affinity' state.

Time-course of antigen-induced airway inflammation in the guinea-pig and its relationship to airway hyperresponsiveness.

The causative relationship between airway inflammation and hyperreactivity is unclear, since inflammatory changes have been examined at one or, at most, a few time-points after antigen challenge in both human asthma and animal models. We have made a detailed investigation of inflammatory and functional changes in the airways up to 8 days after antigen challenge in guinea-pigs. In particular, we examined the hypothesis that eosinophil-derived mediators contribute to tissue damage and the development of airway hyperresponsiveness. Following antigen challenge, the influx of inflammatory cells and mediator release in airway tissue and bronchoalveolar lavage fluid were correlated temporally with histopathological changes in airway tissue and airway responsiveness. Eosinophil influx was demonstrable at 4 h. Eosinophilia peaked after 24 h and persisted for at least 8 days. Parallel increases in the concentrations of major basic protein and eosinophil cationic protein in bronchoalveolar lavage fluid indicated that the eosinophils were activated. Eosinophilia was accompanied by subepithelial oedema and epithelial damage co-localized with major basic protein immunoreactivity. A transient neutrophilia (< 48 h duration) and an increase in neutrophil elastase in bronchoalveolar lavage fluid peaked at 14 h. The proportion of airway macrophages with an activated morphology increased at 8 h and remained markedly elevated until 72 h. Airways were hyperresponsive to histamine at 4 h and for at least 8 days. The antigen-induced airway inflammation resemble in time-course and histopathology that seen in antigen-challenged asthmatics, and indicate that the eosinophil and its cytotoxic proteins may be major mediators of airway mucosal damage and airway hyperresponsiveness.

IgE production, antigen-induced airway inflammation and airway hyperreactivity in the brown Norway rat: the effects of ricin.

Ricin has been shown to enhance IgE production in the rat, probably through inhibition of suppressor T lymphocytes. We have studied further the effects of ricin on IgE titre and have determined its effects on antigen-induced airway inflammation and hyperreactivity in the Brown Norway rat. Immunization with ovalbumin (1-100 micrograms, intraperitoneally) produced dose-related increases in serum antigen-specific IgE titre. Ricin augmented the total IgE titre and caused about a 10-fold increase in the peak antigen-specific IgE titre. In sensitized animals, antigen challenge (three times with aerosolized ovalbumin every second day) caused a significant influx of eosinophils and neutrophils and significant airway hyperreactivity 24 hr after the third challenge. In sensitized animals that had also received ricin, the eosinophil and neutrophil influx was further significantly potentiated and a significant influx of lymphocytes also occurred. Thus, there was a relationship between the degree of sensitization and the magnitude of the inflammatory response. However, the enhanced airway inflammation in ricin-treated animals was not accompanied by a further enhancement of airway hyperreactivity. The present study demonstrates that ricin enhances IgE production and augments an antigen-induced inflammatory pathology but does not potentiate antigen-induced airway hyperreactivity.

Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP-specific phosphodiesterase: comparison with rolipram.

1. We have investigated the inhibitory potency of RP 73401, a novel, highly selective and potent inhibitor of cyclic AMP-specific phosphodiesterase (PDE IV), against partially-purified PDE isoenzymes from smooth muscle and the particulate PDE IV from guinea-pig eosinophils. The inhibitory effects of RP 73401 on the generation of superoxide (.O2-), major basic protein (MBP) and eosinophil cationic protein (ECP) from guinea-pig eosinophils have also been studied. 2. RP 73401 potently inhibited partially-purified cyclic AMP-specific phosphodiesterase (PDE IV) from pig aortic smooth muscle (IC50 = 1.2 nM); it was similarly potent against the particulate PDE IV from guinea-pig peritoneal eosinophils (IC50 = 0.7 nM). It displayed at least a 19000 fold selectivity for PDE IV compared to its potencies against other PDE isoenzymes. Rolipram was approximately 2600 fold less potent than RP 73401 against pig aortic smooth muscle PDE IV (IC50 = 3162 nM) and about 250 times less potent against eosinophil PDE IV (IC50 = 186 nM). 3. Solubilization of the eosinophil particulate PDE IV increased the potency of rolipram 10 fold but did not markedly affect the potency of RP 73401. A similar (10 fold) increase in the PDE IV inhibitory potency of rolipram, but not RP 73401, was observed when eosinophil membranes were exposed to vanadate/glutathione complex (V/GSH). 4. Reverse transcription polymerase chain reaction (RT-PCR), using primer pairs designed against specific sequences in four distinct rat PDE IV subtype cDNA clones (PDE IVA-D), showed only mRNA for PDE IVD in guinea-pig eosinophils. PDE IVD was also the predominant subtype expressed in pig aortic smooth muscle cells. 5. RP 73401 (Kiapp = 0.4 nM) was 4 fold more potent than (+/-)-rolipram (Kiapp = 1.7 nM) in displacing[3H]-(+/-)-rolipram from guinea-pig brain membranes.6. In intact eosinophils, RP 73401 potentiated isoprenaline-induced cyclic AMP accumulation(EC50 = 79 nM). RP 73401 also inhibited leukotriene B4-induced generation of *02- (IC50 = 25 nM), and the release of major basic protein (ICo = 115 nM) and eosinophil cationic protein (IC50 = 7 nM). Rolipram was 3-14 times less potent than RP 73401.7. Thus RP 73401 is a very potent and selective PDE IV inhibitor which suppresses eosinophil function suggesting that it may be a useful agent for the treatment of inflammatory diseases such as asthma. The greatly different inhibitory potencies of rolipram against PDE IV from smooth muscle and eosinophils(in contrast to the invariable effects of RP 73401) are unlikely to be attributable to diverse PDE IV subtypes but suggest distinct interactions of the two inhibitors with the enzyme.

Ricin increases IgE levels and airway inflammation but not hyperresponsiveness in the rat.

The effect of ricin treatment on IgE levels and airway inflammation has been examined in ovalbumin (OA)-sensitized rats. Ricin augmented the total IgE titre and caused about a 10-fold increase in the antigen-specific IgE titre. Repeat antigen challenges (every second day) with an OA aerosol increased the number of eosinophils and neutrophils in bronchoalveolar lavage fluid and produced airway hyperresponsiveness (AHR) 24 h after the third challenge. Ricin pretreatment caused a significantly larger influx of eosinophils, neutrophils and lymphocytes into lavage fluid, but there was no further increase in AHR. The present study demonstrates that ricin augments IgE production and the inflammatory response, but that AHR is unrelated to the number of infiltrating inflammatory cells.

Effects of inhaled lignocaine and adrenaline on capsaicin-induced cough in humans.

BACKGROUND: The hypothesis that adrenaline can augment and/or prolong the antitussive effect of nebulised lignocaine was examined. METHODS: The effect of inhaled lignocaine alone (20 mg) and in combination with adrenaline (400 micrograms) was studied on capsaicin-induced cough in 10 healthy subjects. RESULTS: Cough was significantly reduced between five and 25 minutes by lignocaine. Adrenaline alone had no inhibitory effect and it neither augmented nor prolonged the antitussive effect of lignocaine. The subjective anaesthesia by lignocaine was short lasting (less than 15 minutes) and not altered by adrenaline, suggesting different sensory mechanisms for anaesthesia and cough suppression. Plasma concentrations of lignocaine were low (< 30 ng/ml), not altered by adrenaline, and did not correlate with the local anaesthetic or the antitussive effect. CONCLUSIONS: Lignocaine acts locally in the oropharynx and airways and adrenaline does not alter the effect or absorption of nebulised lignocaine on the human respiratory mucosa.

Fluorescent-based typing of the two short tandem repeat loci HUMTH01 and HUMACTBP2: reproducibility of size measurements and genetic variation in the Swedish population.

The aim of this study was to investigate the reproducibility of genetic typing of two tetrameric short tandem repeat (STR) loci and the extent of genetic variation in the Swedish population. An automated, fluorescent-based Applied Biosystems 373A sequencer was used for typing of the HUMTH01 and HUMACTBP2 loci (also named SE33). The former locus has seven alleles in the size range of 154-174 bp, while the latter is a complex locus with more than 32 alleles in the range of 227-316 bp. Using different fluorescent dyes, polymerase chain reaction (PCR) products from the two STR loci were sized in one lane using an internal size standard. In order to compare within- and between-gel reproducibility of fragment size estimates, a control sample was typed three times on each of 20 gels. Within the gel, the standard deviation (SD) of fragment size variability was less than 0.1 bp for four fragment sizes between 158-291 bp. Standard deviations between gels were slightly higher for the two shorter fragment sizes (HUMTH01), while the larger fragments varied between 0.3 and 0.4 bp (HUMACTBP2). The amount of genetic variation was investigated in samples from three Swedish cities (n = 301). Seven alleles were found at HUMTH01 and the observed heterozygosity was 0.77. At the HUMACTBP2 locus more than thirty alleles were found and the observed heterozygosity was 0.96. The observed genotype frequencies at HUMTH01 and HUMACTBP2 did not deviate significantly from Hardy-Weinberg expectations. No indication of a significant excess of homozygotes was found at any of the loci. We conclude that both HUMTH01 and HUMACTBP2 can be reliably typed using the method described. However, the latter locus requires an allelic ladder to be run on each gel.

Inhaled nicotine in humans: effect on the respiratory and cardiovascular systems.

Inhalation of nicotine (0-64 mg/ml) and capsaicin (2 x 10(-6)-2.5 x 10(-4) M) in 24 healthy nonsmoking subjects produced a concentration-dependent cough response. Two subjects coughed to capsaicin but not to nicotine. The mean (95% confidence interval) nicotine concentrations causing two and five coughs were 5.5 (3.5-8.7) and 15.8 (10.0-25.1) mg/ml, respectively, and were reproducible over 3 different days. Capsaicin inhalation did not alter the response to nicotine and vice versa. Both agents increased respiratory resistance, but the response was more rapid to capsaicin. Inhalation of nicotine (0-8 mg/ml) over 5 min caused increases in heart rate and blood pressure and a decrease in skin temperature. Inhaled ipratropium bromide (0.50 mg) had an antitussive effect and also inhibited the nicotine-induced bronchoconstriction, indicating a vagally mediated effect. Sodium cromoglycate (0.20 mg) did not affect cough or airway resistance changes caused by nicotine. This study shows that inhaled nicotine produces a concentration-dependent cough and airway obstruction in healthy subjects, probably because of stimulation of afferent nerve endings in the bronchial mucosa and mediated through parasympathetic cholinergic pathways. Respiratory reflexes evoked by nicotine are similar to those produced by capsaicin, but it is unclear whether these reflexes are mediated by the same type of sensory nerves.

Selective type IV phosphodiesterase inhibitors as antiasthmatic agents. The syntheses and biological activities of 3-(cyclopentyloxy)-4-methoxybenzamides and analogues.

The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibition of the cytosolic PDE IV from pig aorta have been investigated. As a result, some highly potent and selective PDE IV inhibitors have been identified. The most potent compounds have been further evaluated for their inhibitory potencies against PDE IV obtained from and superoxide O2- generation from guinea pig eosinophils in vitro. Selected compounds have also been examined for their activities in inhibiting histamine-induced bronchospasm in anaesthetized guinea pigs. 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.