Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways.

INTRODUCTION: The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß2-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß2-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological TH2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease. METHODS: After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß2-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function. RESULTS: Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1-/-) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol. CONCLUSION: Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the TH2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.

Características de los pacientes con EPOC tratados en neumología en España según grupos GOLD y fenotipos clínicos GesEPOC / Characteristics of COPD Patients Managed in Respiratory Medicine Departments in Spain, According to GOLD Groups and GesEPOC Clinical Phenotypes

Introducción: El objetivo de este estudio ha sido analizar las características clínicas de los pacientes con EPOC vistos en las consultas generales de neumología, el seguimiento de las guías clínicas y la adecuación en la categorización y en el manejo terapéutico. Método: Estudio multicéntrico, transversal, cuyo objetivo primario es describir el número, intensidad y variabilidad de los síntomas en los pacientes con EPOC. La recogida de los datos fue realizada en 2015 por 300 neumólogos que evaluaron un total de 3.010 pacientes, de los cuales 2.669 (88,6%) fueron válidos para el análisis. Resultados: El 22% eran fumadores activos, destacando un 21 y 17% en los grupos C y D de GOLD y un 17 y 19% en los pacientes exacerbadores de GesEPOC. El 62,3% presentaba comorbilidades asociadas. En el proceso diagnóstico destaca el bajo uso de pruebas como el test de difusión o la medición de volúmenes pulmonares, incluso en los grupos más graves de GOLD o en los fenotipos exacerbadores de GesEPOC. También es minoritario el uso de escalas multidimensionales como BODE (12%) o programas específicos de rehabilitación. El tratamiento se basa en el uso de broncodilatadores y corticoides inhalados, en diferentes combinaciones. El uso de metilxantinas fue minoritario (7%). Conclusiones: En consultas de neumología existe una elevada proporción de pacientes EPOC con baja complejidad y un escaso uso de pruebas neumológicas. Se constata un leve cambio en las pautas terapéuticas y la frecuente asociación con comorbilidades que pueden modificar la presentación clínica del paciente

Introduction: The objective of this study was to analyze the clinical characteristics of COPD patients attending general respiratory clinics, adherence to clinical guidelines, classification accuracy, and therapeutic management. Method: Multicenter, cross-sectional study, with the primary objective of describing the number, intensity, and variability of symptoms in COPD patients. Data were collected in 2015 by 300 pulmonologists who evaluated a total of 3,010 patients, of which 2,669 (88.6%) were eligible for analysis. Results: A total of 22% were active smokers, notably 21% and 17% of GOLD groups C and D, and 17% and 19% of exacerbators in the GesEPOC classification; 62.3% had associated comorbidities. The diagnostic process was characterized by limited use of tests such as diffusion capacity or lung volumes, even in the more severe GOLD groups or the GesEPOC exacerbator phenotypes. The use of multidimensional scales, such as BODE (12%), and specific rehabilitation protocols was also rare. Treatment was based on different combinations of bronchodilators and inhaled corticosteroids. Methylxanthines were used in very few patients (7%). Conclusions: A large proportion of COPD patients seen in respiratory clinics have non-complex disease and pulmonology tests are rarely performed. Our study confirms a slight change in treatments and the frequent association with comorbidities that can modify the clinical presentation of the patient

Eficacia de la cafeína en la extubación de recién nacidos de menos de 32 semanas. Revisión sistemática y estudio observacional / Efficacy of caffeine in extubation of newborns under 32 weeks of age. Systematic revision and observational study

Introducción. En neonatos inmaduros que precisan intubación traqueal para recibir asistencia respiratoria o surfactante exógeno, la extubación puede no ser bien tolerada, siendo preciso reintubar. Objetivo. Evaluar la evidencia científica sobre 1) prevención y tratamiento de la apnea de la prematuridad, 2) prevención del fracaso de la extubación, y 3) registrar y valorar el uso del citrato de cafeína en una UCIN. Métodos. Se realizó una revisión sistemática de la literatura referente al uso del citrato de cafeína en la apnea de la prematuridad. Se realizó un registro de uso de la cafeína y su indicación específica, en la unidad neonatal de nuestro hospital. Resultados. El citrato de cafeína es eficaz y seguro tanto en la profilaxis y tratamiento de la apnea de la prematuridad, como para prevenir el fracaso de la extubación, reduciendo la necesidad de reintubación en un 50%, especialmente con dosis altas (15-20 mg/kg/día). En nuestra unidad, el 85% de los neonatos de menos de 32 sem recibieron tratamiento con cafeína, y en la mitad de casos fue para prevenir el fracaso de la extubación. Conclusiones. En todos los neonatos < 30 sem, y de forma individualizada entre las 30 y 32 sem, se recomienda el uso de citrato de cafeína desde 24 horas antes y durante los 6 días siguientes a la extubación; no siendo preciso determinar de modo sistemático sus niveles sanguíneos. Se recomienda también su uso tras la intubación precoz para administrar surfactante exógeno y extubar. Es aconsejable usar simultáneamente CPAP-n (AU)

Background. Immature neonates requiring tracheal intubation for ventilator support or to receive exogenous surfactant therapy, extubation may not be we1ltolerated been reintubation often required. Methods. A systematic literature review was performed concerning the use of caffeine citrate for prematurity apnea, and more specifically,for the prevention of extubation failure. Moreover, the use of caffeine in infants of less than 32 weeks and its specific indications in our hospital neonatal unit was registered. Results. The use of caffeine is safe and effective in the prophylaxis and treatment of apnea of prematurity, as well as to prevent the extubation failure, (50% reduction), especially if high doses are used (15-20 mg/kg/d). In addition, it is not necessary to routinely measure the blood levels. The simultaneous use of continuous positive airway pressure (CPAP-n) is also recommended. In our unit, 85% of all infants of less than 32 weeks were treated with caffeine citrate, half of them to prevent extubation failure. Conclusions. In all premature infants below 30 week of gestation, and in some between 30 and 32 weeks, the use of caffeine citrate from 24 hours before and for the 6 days following extubation is recommended. The systematic measurement of its blood levels is not required. It is also recommended the simultaneous use of CPAP-n in these infants and in those requiring surfactant to facility their early extubation (AU)

Inhibition of phosphodiesterase-1 attenuates cold-induced pulmonary hypertension.

Chronic exposure to cold caused pulmonary arterial hypertension (cold-induced pulmonary hypertension [CIPH]) and increased phosphodiesterase-1C (PDE-1C) expression in pulmonary arteries (PAs) in rats. The purpose of this study is to investigate a hypothesis that inhibition of PDE-1 would decrease inflammatory infiltrates and superoxide production leading to attenuation of CIPH. Three groups of male rats were exposed to moderate cold (5±1°C) continuously, whereas 3 groups were maintained at room temperature (23.5±1°C, warm; 6 rats/group). After 8-week exposure to cold, 3 groups in each temperature condition received continuous intravenous infusion of 8-isobutyl-methylxanthine (8-IBMX) (PDE-1 inhibitor), apocynin (NADPH oxidase inhibitor) or vehicle, respectively, for 1 week. Cold exposure significantly increased right-ventricular systolic pressure compared with warm groups (33.8±3.2 versus 18.6±0.3 mm Hg), indicating that animals developed CIPH. Notably, treatment with 8-IBMX significantly attenuated the cold-induced increase in right ventricular pressure (23.5±1.8 mm Hg). Cold exposure also caused right-ventricular hypertrophy, whereas 8-IBMX reversed cold-induced right ventricular hypertrophy. Cold exposure increased PDE-1C protein expression, macrophage infiltration, NADPH oxidase activity, and superoxide production in PAs and resulted in PA remodeling. 8-IBMX abolished cold-induced upregulation of PDE-1C in PAs. Interestingly, inhibition of PDE-1 eliminated cold-induced macrophage infiltration, NADPH oxidase activation, and superoxide production in PAs and reversed PA remodeling. Inhibition of NADPH oxidase by apocynin abolished cold-induced superoxide production and attenuated CIPH and PA remodeling. In conclusion, inhibition of PDE-1 attenuated CIPH and reversed cold-induced PA remodeling by suppressing macrophage infiltration and superoxide production, suggesting that upregulation of PDE-1C expression may be involved in the pathogenesis of CIPH.

Phosphodiesterase inhibitors as a new generation of antiprotozoan drugs: exploiting the benefit of enzymes that are highly conserved between host and parasite.

Protozoan infections remain a major unsolved medical problem in many parts of our world. A major obstacle to their treatment is the blatant lack of medication that is affordable, effective, safe and easy to administer. For some of these diseases, including human sleeping sickness, very few compounds are available, many of them old and all of them fraught with toxic side effects. We explore a new concept for developing new-generation antiprotozoan drugs that are based on phosphodiesterase (PDE) inhibitors. Such inhibitors are already used extensively in human pharmacology. Given the high degree of structural similarity between the human and the protozoan PDEs, the vast expertise available in the human field can now be applied to developing disease-specific PDE inhibitors as new antiprotozoan drugs.

La cafeína como un fármaco preventivo de la enfermedad de Parkinson: evidencias epidemiológicas y sustrato experimental / Caffeine as a preventive drug for Parkinson’s disease: epidemiologic evidence and experimental support

Introducción y desarrollo. Los estudios epidemiológicos prospectivos realizados en grandes cohortes de varones (total: 374.003 sujetos) coinciden en que el riesgo de padecer la enfermedad de Parkinson disminuye progresivamente cuanto mayor es el consumo de café y otras bebidas con cafeína. En el caso de las mujeres (total: 345.184 sujetos), el efecto protector de la cafeína sólo se observa en las mujeres con menopausia que no reciben terapia de reemplazo con estrógenos. Estudios con modelos de parkinsonismo agudo en roedores han mostrado que la cafeína reduce la pérdida de las neuronas dopaminérgicas nigroestriatales inducida con las neurotoxinas 6-hidroxidopamina y 1-metil-4-fenil-1,2,3,6-tetrahidropiridina, efecto que parece estar mediado a través del bloqueo de los receptores A2A de adenosina. Recientemente se demostró que las ratas macho tratadas con dosis moderadas de cafeína (5 mg/kg/día) durante seis meses, seguida de un período de abstinencia de cuando menos dos semanas, desarrollaron una mayor resistencia a la catalepsia provocada con el antagonista dopaminérgico haloperidol, posiblemente mediada por un aumento de la transmisión dopaminérgica en el cuerpo estriado. Conclusiones. Se necesitan más estudios para demostrar inequívocamente que la cafeína previene la degeneración de las neuronas dopaminérgicas en modelos animales de parkinsonismo moderado, crónico y progresivo, pues ello podría conducir al descubrimiento de fármacos más eficaces para la prevención de las enfermedades degenerativas del sistema nervioso central asociadas con el envejecimiento (AU)

Introduction and development. Prospective epidemiologic studies performed in large cohorts of men (total: 374,003 subjects) agree in which the risk of suffering Parkinson’s disease diminishes progressively as the consumption of coffee and other caffeinated beverages increases. In the case of women (total: 345,184 subjects) the protective effect of caffeine is only observed in menopausal women which do not receive estrogen replacement therapy. Studies with models of acute parkinsonism in rodents have shown that caffeine reduces the loss of nigrostriatal dopaminergic neurons induced with the neurotoxins 6-hidroxidopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, effect that seems to be mediated through blockade of A2A adenosine receptors. Recently, it was shown that male rats treated with moderate doses of caffeine (5 mg/kg/day) during six months, followed by a withdrawal period of at least two weeks, developed a greater resistance to the catalepsy induced with the dopaminergic antagonist haloperidol, which was possibly mediated by an increase of dopaminergic transmission in the corpus striatum. Conclusions. More studies are needed to demonstrate unequivocally that caffeine prevents the degeneration of dopaminergic neurons in animal models of moderate, chronic, and progressive parkinsonism, since it could lead to the discovery of more effective drugs for the prevention of aging-related degenerative diseases of the central nervous system (AU)

Opciones terapéuticas actualespara la apnea de la prematuridad / Current therapeutic options for the apnea of prematurity

La apnea de la prematuridad es una patología característica de recién nacidos prematuros, que refleja la inmadurez de los mecanismos de control de la respiración. El aumento de la incidencia y la supervivencia de los niños prematuros conlleva quela apnea de la pematuridad sea una patología altamente prevalente en las unidades de cuidados intensivos neonatales. El manejo de esta patología consiste, por una parte, en optimizarlas medidas de cuidado del prematuro y, por otra parte, en la identificación y el tratamiento de las causas subyacentes que puedan empeorar la clínica, como infecciones, anemia, hipoglucemia, ductus arterioso persistente, etc. La estimulación física (kinesioterapia) se emplea frecuentemente, y reduce la apnea de forma significativa. El tratamiento específico incluye el uso de fármacos, como las metilxantinas, y de soporte ventilatorio: presión positiva continua en la vía respiratoria (CPAP), ventilación nasal con presión positiva intermitente (VNPPI) y ventilación mecánica convencional (VMC). La instauración del tratamiento es escalonada, lo mismo que su retirada ante la mejoría clínica, en sentido inverso a su instauración (AU)

Apnea of prematurity is a characteristic pathology in premature newborns, reflex of respiratory system immaturity. The increase of the incidence and survival of premature newborns makes this pathology highly prevalent in the neonatal intensive care units. On one hand, the management of this pathology consists of optimizing the care measures of the premature baby. On the other hand, the identification and treatment of underlying causes that might be worsening the clinic such as infections, anaemia, hypoglycaemia, and persistent arterial ductus, etc. The physical stimulation (kinesiotherapy) is frequently used and reduces the apnea significantly. The specific treatment includes the use of drugs such as methylxanthine, and ventilatory support: CPAP, nasal noninvasive ventilation-INV and CMV. The implementation of the treatment must be spaced out as well as its withdrawal before the clinical improvement, inversely as regards to its implementation (AU)

Treatment of keratoconjunctivitis sicca in rabbits with 3-isobutyl-1-methylxanthine.

OBJECTIVE: To examine the effects of topical 3-isobutyl-1-methylxanthine treatment on tear-film osmolarity, conjunctival goblet-cell densities, and corneal epithelial glycogen levels in a rabbit model for keratoconjunctivitis sicca. METHODS: Keratoconjunctivitis sicca was surgically induced in the right eyes of 16 rabbits. In a masked protocol, eight of these operated-on eyes underwent treatment for 12 weeks with a 3.0-mmol solution of 3-isobutyl-1-methylxanthine. The remaining eight operated-on eyes were left untreated and served as controls. RESULTS: The 3-isobutyl-1-methylxanthine treatment resulted in a rapid and significant decrease in tear osmolarity and sodium (P < .5) and potassium levels (P < .05) and a significant increase in conjunctival goblet-cell densities and corneal epithelial glycogen levels compared with untreated and operated-on controls (P < .001). CONCLUSIONS: 3-Isobutyl-1-methylxanthine rapidly and significantly decreased tear-film osmolarity in this rabbit model for keratoconjunctivitis sicca and restored conjunctival goblet-cell densities and corneal glycogen levels, thus reversing the disease process.

Aminofilina y fenoterol en niños con crisis asmática / Aminophylin and fenoterol in children with asthmatic crisis

El presente estudio compara los efectos clínicos y colaterales de dos esquemas de medicación, fenoterol en MDI (micro dosificador inhalatorio) de 100 urg versus fenoterol en MDI de 100 ugr más aminofilina endovenosa, para el tratamiento de crisis de asma leve-moderadas en población pediátrica. Los parámetros evaluados fueron: puntuación de crisis de asma de Bierman-Pierson, frecuencia cardíaca, presencia de tremor, pico espiratorio forzado (PEF). Además se consignó la aparición de otros efectos colaterales, durante un período de 2 horas. Fueron incluídos cincuenta pacientes: veinticinco para cada esquema en forma randomizada. Se encontró que no hubo diferencia significativa entre los grupos de pacientes en cuanto a sus características al ingreso y el efecto clínico del tratamiento, siendo la mejoría en ambos casos similar. Por otro lado el esquema de fenoterol en MDI más aminofilina endovenosa se asoció a un número mayor de efectos adversos, principalmente gastrointestinales. Se observó además que los puntajes clínicos al ingreso constituyen un factor pronóstico para ambos esquemas

Isbufylline, a new xanthine derivative, inhibits airway hyperresponsiveness and airway inflammation in guinea pigs.

The pharmacological actions of the new xanthine, isbufylline, were evaluated in several models of airway hyperresponsiveness and airway inflammation in guinea pigs. At a dose (106 mumol kg-1 i.p.) providing complete protection against acetylcholine aerosol-induced dyspnea in the guinea pig, isbufylline inhibited platelet activating factor (PAF)- and antigen-induced eosinophil infiltration into bronchoalveolar lavage fluid 24 h after challenge of normal and actively immunized guinea pigs, respectively. In addition, this dose of isbufylline also inhibited capsaicin-induced extravasation of protein into bronchoalveolar lavage fluid. Isbufylline, 4.2 mumol kg-1 i.v., significantly inhibited PAF-induced bronchial hyper-responsiveness to i.v. histamine, without exerting evident bronchodilator activity. On the other hand the bronchodilator, salbutamol, at a dose (10.4 mumol kg-1 i.p.) shown to be equieffective to isbufylline (106 mumol kg-1 i.p.) for blocking acetylcholine aerosol-induced dyspnea, had no protective action against PAF- or antigen-induced eosinophil recruitment in bronchoalveolar lavage fluid, or against capsaicin-induced plasma protein extravasation. Furthermore, salbutamol (3.5 mumol kg-1) significantly potentiated allergen-induced cell infiltration and PAF-induced bronchial hyperresponsiveness. The results suggest that isbufylline can exert significant anti-inflammatory actions in guinea pig airways, in addition to its bronchodilator activity. These pharmacological activities are not shared by the beta 2-adrenoceptor agonist, salbutamol.

Stimulation of tear secretion and treatment of dry-eye disease with 3-isobutyl-1-methylxanthine.

We examined the effect of topically applied 3-isobutyl-1-methylxanthine (IBMX), a known secretagogue, on tear secretion and dry-eye disease in a clinical study. We found that IBMX produced a dose-dependent decrease in tear film osmolarity that was significant at 3.0 mmol/L (P less than .0005) in patients with dry-eye disease. This effect was not blocked by prior administration of proparacaine hydrochloride (P less than .05). Throughout a 4-week, open-label, vehicle-controlled study, IBMX decreased tear film osmolarity significantly, whereas vehicle alone did not. After 4 weeks, mean (+/- SEM) osmolarity in IBMX-treated eyes decreased from 325 +/- 3.2 mOsm/L to 312 +/- 1.8 mOsm/L but remained unchanged in vehicle-treated eyes (323 +/- 4.4 mOsm/L vs 320 +/- 4.2 mOsm/L). In our study, IBMX was significantly more effective than vehicle alone in decreasing rose bengal staining (P less than .02). Hence, topical IBMX stimulated tear secretion and decreased ocular surface disease in patients with dry-eye disease.

Comparison of the effects of isobutylmethylxanthine and milrinone on ischaemia-induced arrhythmias and platelet aggregation in anaesthetized rabbits.

1. The aim of this study was to compare the effects of the non-selective phosphodiesterase (PDE) inhibitor, isobutylmethylxanthine (IBMX) and the selective PDE III inhibitor, milrinone, in a rabbit model of acute myocardial ischaemia. 2. Coronary artery occlusion caused changes in the ST-segment of the ECG and ectopic activity in all control rabbits. Ventricular fibrillation occurred in 10 out of 14 (71%) of these animals. Pretreatment with IBMX 100 micrograms kg-1 plus 10 micrograms kg-1 min-1, starting 10 min before coronary artery occlusion, reduced ischaemia-induced ST-segment changes and ventricular fibrillation occurred in only 10% of this group (n = 10). A similar dose of milrinone had no antiarrhythmic activity, whereas with a lower dose of milrinone, 30 micrograms kg-1 plus 3 micrograms kg-1 min-1 (n = 10), only 30% of rabbits fibrillated and ST-segment changes were attenuated. 3. Acute administration of both IBMX and milrinone reduced arterial blood pressure. With the higher dose of milrinone a significant effect was still present after 10 min of drug infusion. A greater hypotensive response to the higher dose of milrinone was observed in the rabbits which subsequently fibrillated during ischaemia. A marked tachycardia was also observed after administration of the higher dose of milrinone. 4. At the end of the experiment platelet aggregation was studied ex vivo. ADP-induced aggregation was reduced by pretreatment of the rabbits with milrinone but not IBMX. Both PDE inhibitors enhanced the ability of isoprenaline to inhibit ADP-induced platelet aggregation but milrinone was more effective, particularly at the higher dose. The results demonstrate that IBMX was antiarrhythmic but that this activity was not directly related to inhibition of platelet aggregation. Adverse haemodynamic effects may explain the failure of milrinone to have similar activity during myocardial ischaemia.

The effects of 3-isobutyl-methyl-xanthine on experimentally induced ocular inflammation in the rabbit.

The effect of topical administration of 3-isobutyl-methyl-xanthine (IBMX), a potent phosphodiesterase inhibitor, was studied on an experimentally provoked uveitis in rabbits. After presensitization with an intravitreal injection of human serum albumin (HSA), intravenous antigenic challenge induces blood-aqueous barrier breakdown and leukocyte infiltration. The effect of IBMX on the blood-aqueous barrier was determined by scoring the severity of the flare in the anterior chamber and by determination of the levels of ascorbic acid and protein in the aqueous. Treatment with IBMX 1% two times daily, significantly inhibited the breakdown of the blood-aqueous barrier and the increase in PGE2 level of the aqueous humor. There was no effect on leukocyte infiltration. The therapeutic effect of IBMX in blood-aqueous barrier protection is comparable with the effect of topical treatment with the corticosteroid medrysone.

Mimickry of anti-granuloma effect of prostaglandin E by dibutyryl cyclic-AMP and some phosphodiesterase inhibitors.

Local administration of PGE1 to pre-formed inflammatory granulomata of rats results in a decrease of granulomatous tissue and reduction of prostaglandin concentrations in granulomatous exudates. Under the same experimental conditions, a similar correlation between these two effects is observed with dibutyryl cyclic-AMP. An anti-granuloma effect is also achieved with the phosphodiesterase inhibitors, IBMX and RA-233, but not with theophylline, a rather feeble inhibitor of this enzyme. The present findings provide further support for the concept that elevation of cyclic-AMP in cell population(s) within granuloma is a promising line for pharmacological suppression of inflammatory tissue proliferation.