Weak peristalsis with large breaks in chronic cough: association with poor esophageal clearance.

BACKGROUND: Gastroesophageal reflux plays an important role in chronic cough (CC). Whether disturbed esophageal motility contributes to increased esophageal reflux exposure or interferes with swallowed bolus clearance is unclear. This study used high resolution esophageal manometry and impedance (HRIM) together with Chicago Classification, and 24-h impedance pH (MII/pH) to address these questions in patients with CC compared with heartburn (HB). METHODS: A retrospective review of 32 patients with CC (mean age 57 [95% CI: 52-62] years) and 32 patients with symptoms of HB (55 [52-62] years) referred for HRIM and MII/pH between September 2012 and September 2013 was undertaken. KEY RESULTS: Weak peristalsis with large breaks (WPLBs) was observed in 34% of CC patients compared with only 12% of HB patients (p = 0.027). Pathological acid exposure time (AET) was identified in 81% of CC patients with WPLBs compared with 29% without (p = 0.011). Increased AET was associated with prolonged clearance time of refluxed events (p = 0.006) rather than increased number of events. AET correlated with the percentage of peristaltic events with large breaks in CC (ρ = 0.467, p = 0.007). Similar data were obtained for total bolus (acid and non-acid) exposure time. Only one of the CC patients with WPLBs exhibited complete bolus transit (CBT) on swallowing compared with 81% without WPLBs (p < 0.001). Moreover, the percentage of peristaltic events associated with CBT negatively correlated with the percentage of peristaltic events with large breaks (r = -0.653, p < 0.001) in CC. CONCLUSIONS & INFERENCES: One-third of CC patients exhibit WPLBs, which directly impacts on clearance of refluxed events and bolus's swallowed. These observations may have important implications for esophageal-bronchial interaction in CC.

Esophageal spasm: demographic, clinical, radiographic, and manometric features in 108 patients.

Diffuse esophageal spasm (DES) remains insufficiently understood. Here we aimed to summarize the demographic, clinical, radiographic, and manometric features in a large cohort of patients with DES. We identified all consecutive patients diagnosed with DES from 2000 to 2006 at Mayo Clinic Florida. The computerized records of these patients were reviewed to extract relevant information. We performed 2654 esophageal motilities during that period. There were 108 patients with esophageal spasm, and 55% were female. Median age was 71 years. The most common leading symptom was dysphagia in 55, followed by chest pain in 31. Weight loss occurred in 28 patients. The median of time from onset of symptoms to diagnosis was 48 months (range 0-480), with a median of time from the first medical consultation to diagnosis of 8 months (range 0-300). The most frequent comorbidities were hypertension and psychiatric problems. At presentation, 81 patients were taking acid-reducing medications, and 49 patients were taking psychotropic drugs. An abnormal esophagogram was noted in 46 of 76 patients with this test available, but most radiographic findings were nonspecific with the typical 'corkscrew' appearance seen in only three patients. Gastroesophageal reflux disease (GERD) was diagnosed by pH testing or endoscopy in 41 patients. We did not find any difference between the rate of simultaneous contractions or esophageal amplitude between patients with a leading symptom of dysphagia and those with chest pain. DES is an uncommon motility disorder that often goes unrecognized for years. Physicians should be aware of the clinical heterogeneity of DES and consider motility testing early in the course of unexplained esophageal symptoms. Given the high prevalence of GERD in DES, the role of GERD and the impact of acid-reducing therapy in DES deserve further study.

Oesophageal eosinophilic infiltration in patients with noncardiac chest pain.

BACKGROUND: Eosinophilic oesophagitis clinically presents with recurrent episodes of dysphagia and food impaction. Recently, we observed patients with noncardiac chest pain and eosinophilic oesophagitis. AIMS: To estimate the prevalence of abnormal eosinophilic infiltration in noncardiac chest pain patients and examine diagnostic utility of demographic, clinical and endoscopic variables to predict eosinophilic oesophagitis. METHODS: Retrospective study of 171 consecutive patients referred for EGD evaluation of noncardiac chest pain. Endoscopic signs consistent with eosinophilic oesophagitis were recorded. The histological findings were grouped as normal: 0-5 eosinophils/high power field (e/hpf), indeterminate: 6-20 e/hpf, and eosinophilic oesophagitis: ≥21 e/hpf. Abnormal eosinophilic infiltration was defined as ≥6 e/hpf. RESULTS: Abnormal eosinophilic infiltrate was noted in 24 patients (14%). Thirteen (8%) had indeterminate counts, while 11 (6%) had eosinophilic oesophagitis. Compared with normal, those with abnormal oesophageal eosinophilic infiltration were more likely to be male (71% vs. 34%, P=0.001), have allergies (29% vs. 12%, P=0.050), have current GER symptoms (42% vs. 18%, P=0.013), rings (54% vs. 22%, P=0.002), furrows (21% vs. 1%, P<0.001) and abnormal eosinophilic oesophagitis findings on endoscopy (67% vs. 32%, P=0.001). Of the 24 abnormal patients, 23 (96%) were either male or had rings, furrows, or white specks. Conversely, 68 of 69 patients (99%) who were female did not have rings, furrows, or white specks, and endoscopy was normal. Eight patients (33%) with abnormal eosinophilic infiltration had a normal endoscopy. CONCLUSIONS: Eosinophilic oesophagitis should be considered in the evaluation of noncardiac chest pain. Our findings suggest that oesophageal biopsies should be obtained particularly in males with recurrent unexplained chest pain, whether endoscopy is normal or abnormal.

Onset and disappearance rates of gastroesophageal reflux symptoms in the Spanish population, and their impact on quality of life.

BACKGROUND: few studies have reported the onset and disappearance rates of gastroesophageal reflux symptoms (GERS) in the population. AIM: to assess the occurrence and disappearance rates of GERS in Spain, and their impact on health-related quality of life (HRQL). PARTICIPANTS AND METHODS: participants were selected at random from the general population of Madrid in age and sex strata. They were interviewed at home twice, 6 months apart. Heartburn, acid regurgitation and consultation were assessed with the gastroesophageal reflux questionnaire, and HRQL with the SF-36. RESULTS: 709 individuals were included, and 451 (63.6%) were re-interviewed 6 months later. Among the 325 individuals without GERS, 9 developed weekly symptoms (2.2% [95% CI: 0.8, 3.4%]); 2 (22%) consulted because of GERS. Among the 34 subjects reporting weekly GERS initially, 26 did not report them at 6-months. Onset of GERS was associated with worsening scores in the physical summary of SF-36 (delta = -6.6 [95% CI: -11.8, -1.42]), while disappearance with an improved score (delta = -3.0 [95% CI: 0.0, 5.9]). CONCLUSION: despite the lower prevalence of GERS in Spain, the occurrence rate is 2.2% in 6 months; however symptoms disappeared in more than half of subjects six months later. Developing GERS was associated with reduced HRQL, and their disappearance with improvement.

Onset and disappearance rates of gastroesophageal reflux symptoms in the Spanish population, and their impact on quality of life

Background: few studies have reported the onset and disappearancerates of gastroesophageal reflux symptoms (GERS) inthe population.Aim: to assess the occurrence and disappearance rates ofGERS in Spain, and their impact on health-related quality of life(HRQL).Participants and methods: participants were selected atrandom from the general population of Madrid in age and sexstrata. They were interviewed at home twice, 6 months apart. Heartburn,acid regurgitation and consultation were assessed withthe gastroesophageal reflux questionnaire, and HRQL with theSF-36.Results: 709 individuals were included, and 451 (63.6%)were re-interviewed 6 months later. Among the 325 individualswithout GERS, 9 developed weekly symptoms (2.2% [95% CI:0.8, 3.4%]); 2 (22%) consulted because of GERS. Among the 34subjects reporting weekly GERS initially, 26 did not report themat 6-months. Onset of GERS was associated with worseningscores in the physical summary of SF-36 (delta = -6.6 [95%CI: -11.8, -1.42]), while disappearance with an improved score(delta = -3.0 [95% CI: 0.0, 5.9]).Conclusion: despite the lower prevalence of GERS in Spain,the occurrence rate is 2.2% in 6 months; however symptoms disappearedin more than half of subjects six months later. DevelopingGERS was associated with reduced HRQL, and their disappearancewith improvement(AU)

A potent and selective p38 inhibitor protects against bone damage in murine collagen-induced arthritis: a comparison with neutralization of mouse TNFalpha.

BACKGROUND AND PURPOSE: The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-alpha (TNFalpha) and is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using the novel p38 inhibitor Org 48762-0, we investigated the therapeutic potential of p38 inhibition and compared this to anti-mouse (m)TNFalpha antibody treatment in murine collagen-induced arthritis (CIA). EXPERIMENTAL APPROACH: Pharmacological profiles of Org 48762-0 were characterized in kinase assays, cellular assays and in lipopolysaccharide (LPS)-induced inflammation in mice. The effects of Org 48762-0 and of mTNFalpha-neutralization on established arthritis were examined in murine CIA. KEY RESULTS: Org 48762-0 potently inhibited p38alpha kinase with a high degree of kinase selectivity. In cellular assays, Org 48762-0 reduced LPS-induced TNFalpha release. Oral administration of Org 48762-0 in mice showed drug-like pharmacokinetic properties and inhibited LPS-induced cytokine production. These pharmacological characteristics of Org 48762-0 prompted a comparison of therapeutic efficacy with mTNFalpha-neutralization in CIA. Org 48762-0 and anti-mTNFalpha antibody treatment equally inhibited development of arthritis when evaluated macroscopically. Radiological analyses revealed protection against bone damage for both treatments, although statistical difference was reached with Org 48762-0 treatment only. Further, micro-computed tomographical and histopathological analyses confirmed the protective effects of Org 48762-0 on joint damage. CONCLUSIONS AND IMPLICATIONS: Pharmacological targeting of p38 kinase provided good protection against joint tissue damage in CIA. In our experiments, neutralization of mTNFalpha produced less prominent suppression of bone damage. Our data suggest a therapeutic potential for selective and potent p38 inhibitors in RA.

[Spanish physicians point of view on irritable bowel syndrome (IBS). Results of a Delphi survey]. / Opinión de los médicos españoles sobre el síndrome de intestino irritable: resultados de un estudio utilizando el método Delphi.

INTRODUCTION: lack of evidence in most clinical situations regarding irritable bowel syndrome (IBS) enhances the importance of an expert s opinion, which will guide management and even the concept underlying the disease. OBJECTIVE: to delve into the knowledge and degree of agreement on main clinical skills for this syndrome among physicians involved in its management. MATERIAL AND METHOD: two rounds of a Delphi survey were conducted on 100 physicians: general practitioners (GPs) and gastroenterologists. The questionnaire evaluated agreement among participants in some aspects regarding the definition, diagnosis, and treatment of IBS. RESULTS: fifty-five percent of participants completed the two-round survey. Agreement was achieved regarding the definition of typical symptoms and red flags characterizing IBS. Although there was no consensus regarding the appropriate management of patients without alarm symptoms, the performance of a colonoscopy on any patient presenting red flags was suggested. Patients were thought to require a wider examination when older than 40. A well defined line of IBS treatment was not found, albeit most physicians tended to choose it depending on the main complaint. CONCLUSION: interviewed physicians showed adequate theoretical knowledge of IBS, but lack of uniformity on diagnosis and treatment approach reflects the controversial day-by-day management of this syndrome.

Opinión de los médicos españoles sobre el síndrome de intestino irritable: resultados de un estudio utilizando el método Delphi / Spanish physicians’ point of view on irritable bowel syndrome (IBS). Results of a Delphi survey

Introducción: el síndrome del intestino irritable (SII) es una patología controvertida, donde ante la escasez de evidencia científica las recomendaciones sobre su manejo clínico y su definición vienen determinadas por métodos de consenso de expertos. Objetivo: obtener la opinión de los médicos de nuestro país implicados en el manejo de pacientes con SII y conocer los puntos de acuerdo en las principales cuestiones clínicas que plantea. Material y métodos: se realizó un estudio Delphi a nivel nacional mediante dos envíos a 100 médicos de atención primaria y gastroenterólogos. El cuestionario incluía preguntas sobre el concepto, diagnóstico y tratamiento del SII, evaluando el grado de acuerdo entre los participantes. Resultados: el 55% de los encuestados completó los dos envíos. Se obtuvo acuerdo respecto a los síntomas que caracterizan al SII y los de alarma. No existió una actitud clara ante el paciente sin síntomas de alarma, pero sí acuerdo respecto a la realización de colonoscopia en su presencia. Se señaló la necesidad de realizar estudios complementarios en mayores de 40 años. En el tratamiento no encontramos una actitud uniforme, aunque parece existir una orientación diferente según el síntoma predominante. Conclusiones: los médicos participantes en el estudio demuestran a través de sus respuestas un buen conocimiento conceptual del SII, si bien las discrepancias observadas en las cuestiones sobre diagnóstico y tratamiento demuestran la complejidad y falta de uniformidad que existe en el manejo diario de este síndrome

Introduction: lack of evidence in most clinical situations regarding irritable bowel syndrome (IBS) enhances the importance of an expert’s opinion, which will guide management and even the concept underlying the disease. Objective: to delve into the knowledge and degree of agreement on main clinical skills for this syndrome among physicians involved in its management. Material and method: two rounds of a Delphi survey were conducted on 100 physicians: general practitioners (GPs) and gastroenterologists. The questionnaire evaluated agreement among participants in some aspects regarding the definition, diagnosis, and treatment of IBS. Results: fifty-five percent of participants completed the tworound survey. Agreement was achieved regarding the definition of typical symptoms and red flags characterizing IBS. Although there was no consensus regarding the appropriate management of patients without alarm symptoms, the performance of a colonoscopy on any patient presenting red flags was suggested. Patients were thought to require a wider examination when older than 40. A well defined line of IBS treatment was not found, albeit most physicians tended to choose it depending on the main complaint. Conclusion: interviewed physicians showed adequate theoretical knowledge of IBS, but lack of uniformity on diagnosis and treatment approach reflects the controversial day-by-day management of this syndrome

Has the identification of rectal hypersensitivity any implication in the clinical outcome of irritable bowel syndrome?

BACKGROUND: Sixty percent of patients with irritable bowel disease (IBS) are hypersensitive to rectal distension. It is uncertain to what extend the identification of this abnormality has an impact in the clinical outcome. OBJECTIVE: to evaluate if rectal hypersensitivity is associated with a different clinical outcome, prognosis and use of medical resources. MATERIAL AND METHODS: Patients with IBS (Rome II criteria) who underwent a rectal distension study at least one year before were eligible if they have not been included in any research protocol since then. We reviewed how many times in the last year they came to emergency room, underwent an endoscopy, and consulted a gastroenterologist or other medical physician for any reason. Also, a telephone interview was done by a gastroenterology fellow using a structured questionnaire to evaluate the frequency and severity of their symptoms in the last year and last month. RESULTS: A total of 52 patients were eligible and 38 were included. Fourteen were not included because inability to made a phone contact or did not consent to phone interview. Twenty six patients were hypersensitive and 12 normosensitive. Both groups had similar symptoms (frequency and severity) but hypersensitive patients visited less to the gastroenterologist (1.2 +/- 0.2 vs. 2.9 +/- 0.6 times yearly, p < 0.01). CONCLUSION: Identification of rectal hypersensitivity to distension is associated to less consultation to gastroenterologist, although severity and frequency of symptoms are not modified. Finding of an objective explanation of the symptoms seems to help patients to understand their disease, leading to a decrease in resources use.

¿Tiene alguna repercusión clínica la identificación de hipersensibilidad en el síndrome de intestino irritable? / Has the identification of rectal hypersensitivity any implication in the clinical outcome of irritable bowel syndrome?

Introducción: el 60% de los pacientes con SII tienen hipersensibilidad a la distensión rectal. Se desconoce si la identificación de esta alteración puede modificar su evolución. Objetivo: evaluar si la hipersensibilidad a la distensión rectal se asocia con un diferente pronóstico respecto a la presentación de síntomas y la utilización de recursos sanitarios en pacientes con SII. Material y métodos: se incluyeron pacientes con SII según criterios de Roma II, que habían sido sometidos a un estudio de distensión rectal. Se recogieron datos de los registros informáticos sobre asistencia a consultas especializadas, realización de endoscopias, asistencia a urgencias e ingresos hospitalarios. Además, se realizó entrevista telefónica en la que se interrogó acerca de la existencia de síntomas a lo largo del último año y último mes (características, duración y severidad). Resultados: se evaluaron 38 pacientes, 26 con hipersensibilidad en el estudio de distensión basal y 12 normosensibles. En el momento de la recogida de datos (registro informático y entrevista telefónica) el seguimiento medio era de 2,39 años después del estudio de distensión. Los sujetos hipersensibles presentaron una clínica similar a aquellos normosensibles. Se registró una menor tasa de frecuentación anual en las consultas de Aparato Digestivo (1,2 ± 0,2 vs. 2,9 ± 0,6, p < 0,01) por parte de los pacientes hipersensibles sin existir diferencias en el resto de variables estudiadas. Conclusión: la identificación de hipersensibilidad visceral en pacientes con SII conlleva una notable reducción de las consultas al gastroenterólogo, sin que esto pueda explicarse por la mejoría de los síntomas, ni por una menor tendencia a realizar otras consultas médicas

Background: sixty percent of patients with irritable bowel disease (IBS) are hypersensitive to rectal distension. It is uncertain to what extend the identification of this abnormality has an impact in the clinical outcome. Objective: to evaluate if rectal hypersensitivity is associated with a different clinical outcome, prognosis and use of medical resources. Material and methods: patients with IBS (Rome II criteria) who underwent a rectal distension study at least one year before were eligible if they have not been included in any research protocol since then. We reviewed how many times in the last year they came to emergency room, underwent an endoscopy, and consulted a gastroenterologist or other medical physician for any reason. Also, a telephone interview was done by a gastroenterology fellow using a structured questionnaire to evaluate the frequency and severity of their symptoms in the last year and last month. Results: a total of 52 patients were eligible and 38 were included. Forteen were not included because inability to made a phone contact or did not consent to phone interview. Twenty six patients were hypersensitive and 12 normosensitive. Both groups had similar symptoms (frequency and severity) but hypersensitive patients visited less to the gastroenterologist (1.2 ± 0.2 vs. 2.9 ± 0.6 times yearly, p < 0.01). Conclusion: identification of rectal hypersensitivity to distension is associated to less consultation to gastroenterologist, although severity and frequency of symptoms are not modified. Finding of an objective explanation of the symptoms seems to help patients to understand their disease, leading to a decrease in resources' use

Synthesis and SAR of a new series of COX-2-selective inhibitors: pyrazolo[1,5-a]pyrimidines.

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.

Synthesis and structure-activity relationship of a new series of potent AT1 selective angiotensin II receptor antagonists: 5-(biphenyl-4-ylmethyl)pyrazoles.

The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure-activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l] methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.

In vitro pharmacological characterization of a new selective angiotensin AT1 receptor antagonist, UR-7280.

UR-7280 (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l]methyl]-1H-pyrazole-4-carboxylic acid) is a new and potent angiotensin AT1-selective receptor antagonist. Binding studies in rat liver membranes showed that UR-7280 is an apparently competitive antagonist. However, in rabbit aorta this compound antagonized the angiotensin II-induced contractile response in an insurmountable way, causing a significant reduction of the maximal response. Additional binding studies evidenced that UR-7280 has a slowly reversible binding profile, consistent with its functional properties in rabbit aorta. The results obtained with a series of structural analogues of UR-7280 demonstrated a relationship between the size of the pyrazole 3-substituent and the surmountable or insurmountable mode of antagonism, indicating that this position may play a key role in the interaction between the antagonist and the angiotensin AT1 receptor.

Diphenylpropionic acids as new AT1 selective angiotensin II antagonists.

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.

[(3-Pyridylalkyl)piperidylidene]benzocycloheptapyridine derivatives as dual antagonists of PAF and histamine.

A series of [(3-pyridylalkyl)piperidylidene]- and (nicotinoylpiperidylidene)benzocycloheptapyridine derivatives, Ia,b, were prepared and evaluated for PAF antagonist and H1 antihistamine activity. PAF antagonist activity was investigated by the in vitro PAF-induced platelet aggregation assay (PPA) and the in vivo PAF-induced hypotension test in rats (PH) and mortality test in mice (PM). For the evaluation of H1 antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) and the in vivo histamine-induced hypotension test (HH) in normotensive rats were used. The potential antiallergic activity of the compounds was evaluated using the active anaphylactic shock test in mice. These compounds are structurally related to loratadine (1) and were generated by replacement of the ethoxycarbonyl group of 1 with substituted 3-pyridylmethyl and nicotinoyl moieties. Both anti-PAF and H1 antihistamine activities have shown a high dependence on the exact nature and position of the substituent in the pyridine ring. Optimum structure 19 (UR-12592) incorporating a (5-methyl-3-pyridyl)methyl radical displayed an unique dual activity inhibiting both PAF-induced effects (PPA, IC50 = 3.7 microM; PH, ID50 = 0.44 mg/kg iv; PM, ID50 = 1.9 mg/kg po) and histamine-induced effects (HC, IC50 = 3.9 nM; HH, ID50 = 1.4 mg/kg iv). Furthermore, 19 was highly active in the passive cutaneous anaphylactic shock in rats (ID50 = 1.2 mg/kg po) and strongly protected mice and rats from mortality induced by endotoxin (ID50 = 1.2 and 0.5 mg/kg iv, respectively). Compound 19 showed itself to be devoid of CNS depressant effects, neither modifying spontaneous motor activity nor prolonging barbiturate-sleeping time in mice at a dose of 100 mg/kg po, and is now under development.

Synthesis and structure-activity relationships of 1-acyl-4-((2-methyl-3-pyridyl)cyanomethyl)piperazines as PAF antagonists.

A second generation of (cyanomethyl)piperazines, 1-acyl-4-((2-methyl-3-pyridyl)cyanomethyl)-piperazines, with increased oral activity was prepared and evaluated in vitro in a PAF-induced platelet aggregation assay (PAG) and in vivo in a PAF-induced hypotension test in normotensive rats (HYP). Oral activity was ascertained through a PAF-induced mortality test in mice (MOR). Attachment of a methyl group at position 2 of our earlier pyridine derivatives resulted in an improvement of 1 order of magnitude or greater in the ID50 of the oral test. Three different types of acyl substituents of similar potency emerge from this work: N-(diphenylmethylamino)acetyl, 3-substituted 3-hydroxy-3-phenylpropionyl, and N-substituted 3-amino-3-phenylpropionyl groups. The most interesting compounds, 26 (UR-12460, PAG IC50 = 0.040 microM, HYP, ID50 = 0.021 mg/kg i.v., MOR, ID50 = 0.30 mg/kg po) and 58 (UR-12519, PAG IC50 = 0.041 microM, HYP, ID50 = 0.015 mg/kg i.v., MOR, ID50 = 0.044 mg/kg po), compare favorably with WEB-2086. Compounds 26 and 58 were also tested in active anaphylactic shock (AAS) and endotoxin-induced mortality (EIM) tests. On the basis of these data, compounds 26 and 58 have been selected for further pharmacological development.

2,2-Dialkylnaphthalen-1-ones as new potassium channel activators.

A new series of 2,2-dialkylnaphthalen-1-one potassium channel activators has been prepared, and their in vitro relaxant activities in isolated rat portal vein and guinea pig tracheal spirals as well as their oral antihypertensive effect in spontaneously hypertensive rats have been evaluated. The group of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethylnaphthalen -1- ones with an electron-withdrawing substituent at the 6-position contain the most active compounds and 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile, 17f (UR-8225), has been selected for further pharmacological development.

(Pyridylcyanomethyl)piperazines as orally active PAF antagonists.

A series of (pyridylcyanomethyl)piperazines was prepared and evaluated for PAF-antagonist activity. Compounds were tested in vitro in a PAF-induced platelet aggregation assay and in vivo in a PAF-induced hypotension test in normotensive rats. Oral activity was ascertained through a PAF-induced mortality test in mice. The main structure-activity trends of the series were established. Activity was mainly found in four skeletons: 1-acyl-4-(3-pyridylcyanomethyl)piperazine, 1-acyl-4-(4-pyridylcyanomethyl)piperazine, 1-acyl-4-(3-pyridylcyanomethyl)piperidine, and 1-acyl-4-cyano-4-(3-pyridylamino)piperidine. The acyl substituents, diphenylacetyl and 3,3-diphenylpropionyl, provided the most active compounds, and the introduction of an amine or hydroxy group in the 3,3-diphenylpropionyl substituent led to further improvement in oral activity. As a result, three of the most active compounds (100, 114, and 115) have been selected for further pharmacological development.