ABSTRACT
BACKGROUND: Nasal H(3) receptors might have a role in mediating the effects of histamine in patients with allergic rhinitis. OBJECTIVE: This study explored the effect of the potent oral H(3) receptor antagonist PF-03654746 in combination with an oral H(1) receptor antagonist on the objective (acoustic rhinometry) and subjective (symptoms) responses to nasal allergen challenge. METHODS: Twenty patients with out-of-season allergic rhinitis displaying a 30% or greater decrease in minimum nasal cross-sectional area (A(min)) after bolus (ragweed) complete nasal allergen challenge at screening were studied by using a randomized, double-blind, single-dose, 4-way crossover design. Treatments included 10 mg of PF-03654746 plus 60 mg of fexofenadine (group 1), 1 mg of PF-03654746 plus 60 mg of fexofenadine (group 2), 60 mg of fexofenadine/120 mg of pseudoephedrine (group 3), and placebo (group 4). After dosing, subjects underwent complete nasal allergen challenge. Nasal symptom scores (no. of sneezes and 0- to 5-point scores for severity of congestion, itching, and rhinorrhea), A(min) (in square centimeters), and nasal volume (in cubic centimeters) were recorded 15, 30, 45, and 60 minutes after allergen. There was a minimum 10-day washout between periods. RESULTS: The following symptom scores were significantly (P ≤ .05) reduced by active treatments versus placebo: group 1, congestion of -0.7 (SE, 0.3), itching of -1.0 (SE, 0.3), rhinorrhea of -1.3 (SE, 0.3), and sneeze of -8.8 (SE, 1.5); group 2, itching of -0.6 (SE, 0.3), rhinorrhea of -0.8 (SE, 0.3), and sneeze of -9.1 (SE, 1.5); and group 3, rhinorrhea of -0.7 (SE, 0.3) and sneeze of -7.0 (SE, 1.5). There was no significant effect of any treatment on mean A(min) proportion or nasal volume proportion after nasal allergen challenge. CONCLUSIONS: In combination with fexofenadine, single doses of PF-03654746 caused a reduction in allergen-induced nasal symptoms. H(3) receptor antagonism might be a novel therapeutic strategy to further explore in patients with allergic rhinitis.
Subject(s)
Anti-Allergic Agents/therapeutic use , Cyclobutanes/therapeutic use , Histamine H1 Antagonists, Non-Sedating/therapeutic use , Histamine H3 Antagonists/therapeutic use , Pyrrolidines/therapeutic use , Rhinitis, Allergic, Seasonal/drug therapy , Terfenadine/analogs & derivatives , Adult , Ambrosia/immunology , Anti-Allergic Agents/adverse effects , Cross-Over Studies , Cyclobutanes/adverse effects , Double-Blind Method , Drug Combinations , Female , Histamine H1 Antagonists, Non-Sedating/adverse effects , Histamine H3 Antagonists/adverse effects , Humans , Male , Middle Aged , Nasal Provocation Tests , Pyrrolidines/adverse effects , Skin Tests , Terfenadine/adverse effects , Terfenadine/therapeutic use , Young AdultABSTRACT
RATIONALE: Prostacyclin analogs, used to treat idiopathic pulmonary arterial hypertension (IPAH), are assumed to work through prostacyclin (IP) receptors linked to cyclic AMP (cAMP) generation, although the potential to signal through peroxisome proliferator-activated receptor-γ (PPARγ) exists. OBJECTIVES: IP receptor and PPARγ expression may be depressed in IPAH. We wished to determine if pathways remain functional and if analogs continue to inhibit smooth muscle proliferation. METHODS: We used Western blotting to determine IP receptor expression in peripheral pulmonary arterial smooth muscle cells (PASMCs) from normal and IPAH lungs and immunohistochemistry to evaluate IP receptor and PPARγ expression in distal arteries. MEASUREMENTS AND MAIN RESULTS: Cell proliferation and cAMP assays assessed analog responses in human and mouse PASMCs and HEK-293 cells. Proliferative rates of IPAH cells were greater than normal human PASMCs. IP receptor protein levels were lower in PASMCs from patients with IPAH, but treprostinil reduced replication and treprostinil-induced cAMP elevation appeared normal. Responses to prostacyclin analogs were largely dependent on the IP receptor and cAMP in normal PASMCs, although in IP(-/-) receptor cells analogs inhibited growth in a cAMP-independent, PPARγ-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARγ agonist and inhibited (⼠60%) by the PPARγ antagonist GW9662. This coincided with increased PPARγ expression in the medial layer of acinar arteries. CONCLUSIONS: The antiproliferative effects of prostacyclin analogs are preserved in IPAH despite IP receptor down-regulation and abnormal coupling. PPARγ may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.
Subject(s)
Hypertension, Pulmonary/physiopathology , Muscle, Smooth, Vascular/cytology , PPAR gamma/physiology , Receptors, Epoprostenol/physiology , Animals , Antihypertensive Agents/pharmacology , Blotting, Western , Cell Proliferation , Down-Regulation/physiology , Epoprostenol/analogs & derivatives , Epoprostenol/pharmacology , HEK293 Cells , Humans , Iloprost/pharmacology , Immunohistochemistry , Mice , PPAR gamma/metabolism , Prostaglandins, Synthetic/pharmacology , Rosiglitazone , Thiazolidinediones/pharmacology , Vasodilator Agents/pharmacologyABSTRACT
BACKGROUND: Morbidity in COPD results from a combination of factors including hypoxia-induced pulmonary hypertension, in part due to pulmonary vascular remodelling. Animal studies suggest a role of angiotensin II and acute studies in man concur. Whether chronic angiotensin-II blockade is beneficial is unknown. We studied the effects of an angiotensin-II antagonist losartan, on haemodynamic variables, exercise capacity and symptoms. METHODS: This was a double-blind, randomized, parallel group, placebo- controlled study of 48 weeks duration. Forty patients with COPD and pulmonary hypertension (Tran tricuspid pressure gradient (TTPG) = 30 mmHg) were randomised to losartan 50 mg or placebo. Changes in TTPG were assessed at 3, 6 and 12 months. RESULTS: There was a trend for TTPG to increase in the placebo group (baseline 43.4 versus 48.4 mmHg at endpoint) and stay constant in the losartan group (baseline 42.8 versus 43.6 mmHg). More patients in the losartan group (50%) than in the placebo group (22%) showed a clinically meaningful reduction in TTPG at any timepoint; these effects seemed more marked in patients with higher baseline TTPG. There were no clear improvements in exercise capacity or symptoms. CONCLUSION: In this 12-month pilot study, losartan 50 mg had no statistically significant beneficial effect on TTPG, exercise capacity or symptoms in pulmonary hypertension secondary to obstructive disease. A sub-group of patients with higher TTPG may benefit.
Subject(s)
Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/etiology , Losartan/therapeutic use , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/drug therapy , Aged , Aged, 80 and over , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Double-Blind Method , Exercise Tolerance/drug effects , Humans , Hypertension, Pulmonary/diagnosis , Male , Middle Aged , Pilot Projects , Placebo Effect , Pulmonary Disease, Chronic Obstructive/diagnosis , Quality of Life , Treatment OutcomeABSTRACT
We investigated the effects of prostacyclin analogs and isoform-selective phosphodiesterase (PDE) inhibitors, alone and in combination, on pulmonary vascular remodeling in vitro and in vivo. Vascular smooth muscle cells (VSMC) isolated from pulmonary (proximal and distal) and systemic circulations demonstrated subtle variations in expression of PDE isoform mRNA. However, using biochemical assays, we found PDE3 and PDE4 isoforms to be responsible for the majority of cAMP hydrolysis in all VSMC. In growth assays, the prostacyclin analogs cicaprost and iloprost inhibited mitogen-induced proliferation of VSMC in a cAMP-dependent manner. In addition, isoform-selective antagonists of PDEs 1, 3, or 4 inhibited VSMC proliferation, an effect that synergized with the effect of prostacyclin analogs. The inhibitory effects were greater in cells isolated from pulmonary circulation. In an in situ perfused rat lung preparation, administration of prostacyclin analogs or the PDE inhibitors vinpocetine (PDE1), cilostamide (PDE3), or rolipram (PDE4), but not EHNA (PDE2), attenuated acute hypoxic vasoconstriction (HPV). Combinations of agents led to a greater reduction in HPV. Furthermore, during exposure to hypoxia for 13 days, Wistar rats were treated with iloprost, rolipram, cilostamide, or combinations of these agents. Compared with normoxic controls, hypoxic animals developed pulmonary hypertension and distal pulmonary artery muscularization. These parameters were attenuated by iloprost+cilostamide, iloprost+rolipram, and cilostamide+rolipram but were not significantly affected by single agents. Together, these findings provide a greater understanding of the role of cAMP PDEs in VSMC proliferation and provide rationale for combined use of prostacylcin analogs plus PDE3/4 inhibitors in treatment of pulmonary vascular remodeling.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Hypoxia/physiopathology , Phosphodiesterase Inhibitors/pharmacology , Prostaglandins I/pharmacology , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Animals , Aorta/cytology , Cell Division , Cells, Cultured , Chronic Disease , Coronary Vessels/cytology , Cyclic AMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 1 , Drug Synergism , Intracellular Membranes/metabolism , Isoenzymes/metabolism , Lung/metabolism , Lung/physiopathology , Male , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/enzymology , Myocytes, Smooth Muscle/metabolism , Phosphoric Diester Hydrolases/metabolism , Rats , Rats, Inbred WKY , Renal Artery/cytology , Reverse Transcriptase Polymerase Chain Reaction , VasodilationABSTRACT
This study presents data on limited surgical management of malignant pleural mesothelioma. We reviewed retrospectively 70 cases of the disease managed surgically over a 10 year period. Fifteen patients received only diagnostic direct pleural biopsy, 40 had video-assisted thoracoscopic, pleural biopsy and talc pleurodesis while 15 patients underwent thoracotomy and pleurectomy for disease confined to the pleura. There were two in-hospital deaths. Actuarial survival was significantly longer in the thoracotomy group (median 14 months vs. 6 months in the other two groups, P < 0.03). Survival after limited surgical management of malignant mesothelioma is comparable to a previously reported more radical surgical approach.
ABSTRACT
The normal adult pulmonary circulation is a low-pressure, high-capacity circuit. Pulmonary vascular resistance is regulated by alveolar oxygen tension, potassium channels and a variety of locally produced and circulating vasoactive factors. Perturbations of these systems may contribute to the pathogenesis of pulmonary hypertension. Recently, mutations in BMPR2 and ALK-1, genes that encode members of the transforming growth factor-beta (TGF-beta) receptor superfamily, have been found in patients with primary pulmonary hypertension. These observations provide a novel insight into the pathogenesis of primary pulmonary hypertension, and emphasize the importance of the integrity of the TGF-beta receptor family in the maintenance of normal pulmonary vascular structure and function. This review discusses the latest developments in the field of pulmonary vascular biology and the prospects for improving the treatment of pulmonary hypertension.