Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterase-4 isoenzymes have absolute specificity for cyclic adenosine-3',5'-monophosphate and are considered potential therapeutic targets for the treatment of chronic inflammatory disorders, such as chronic obstructive pulmonary disease, with small-molecule inhibitors. Several selective phosphodiesterase-4 inhibitors are in clinical trials of chronic obstructive pulmonary disease, including cilomilast and roflumilast. Despite some encouraging data from phase III clinical trials, the current generation of phosphodiesterase-4 inhibitors is hampered by a low therapeutic ratio. Indeed, a major obstacle is their propensity to evoke non-steroid-like side effects, of which nausea, diarrhea, abdominal pain, vomiting, and dyspepsia are the most common. In addition, a particularly worrying potential toxicity of phosphodiesterase-4 inhibitors, also shared by phosphodiesterase-3 inhibitors and other vasodilators, is arteritis/periarteritis. One potential means of improving the therapeutic ratio and safety of phosphodiesterase-4 inhibitors may lie in the development of compounds that have broader phosphodiesterase specificity. Of the 11 phosphodiesterase families that have been unequivocally identified, dual-specificity compounds that inhibit phosphodiesterase-4 and phosphodiesterase-1, phosphodiesterase-3, or phosphodiesterase-7 may offer the best opportunities to enhance clinical efficacy.
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PMID:Phosphodiesterase-4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease. 1626 57

Phosphodiesterase (PDE)4 inhibitors are a novel class of drugs in development for the treatment of inflammatory airways diseases, including asthma, allergic rhinitis and chronic obstructive pulmonary disease. PDE4 inhibitors are potent anti-inflammatory agents both in vitro and in vivo, but few have successfully proceeded to phase II and III clinical trials, as a result of insufficient clinical efficacy and unacceptable side effects, including nausea and emesis, which have hampered their progression. A greater understanding of the molecular biology of PDE4 has led to the development of efficacious compounds with fewer side effects. This review focuses on how selective PDE4 inhibitors can advance the treatment of airways diseases and deal with the challenges that lie ahead.
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PMID:Selective phosphodiesterase 4 inhibitors in the treatment of allergy and inflammation. 1631 35

Roflumilast is an inhibitor of phosphodiesterase- IV (PDE4), a cellular enzyme that is linked to airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). In clinical trials, roflumilast produced significant improvements in FEV1 (forced expiratory volume in one second) and PEF (peak expiratory flow) compared with low-dose inhaled beclomethasone in asthma patients, and compared with placebo in COPD patients. Roflumilast reduced the use of rescue medication in both populations. COPD patients on roflumilast experienced fewer exacerbations. The most common adverse effects reported in roflumilast trials were diarrhea, nausea, headache, and abdominal pain. Evidence is only available in non-peer-reviewed format abstracts. Most of the measures used are markers of clinical effects as opposed to clinical outcomes. More studies are needed to determine the role of roflumilast in the treatment of asthma and COPD.
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PMID:Roflumilast for asthma and chronic obstructive pulmonary disease. 1631 27

Chronic obstructive pulmonary disease (COPD) is a multicomponent, chronic inflammatory disease of the lungs with systemic complications. The majority of the inflammation occurs in the peripheral airways and lung parenchyma. It is a progressive disease, leading to disability and eventual death, despite conventional therapy. Inflammatory activity can be reduced by increasing intracellular cyclic adenosine-3',5'-monophosphate (cAMP) through inhibition of phosphodiesterase (PDE) IV, the principal PDE isoenzyme within pro-inflammatory cells, including eosinophils, mast cells, macrophages, lymphocytes, neutrophils and epithelial cells. PDE IV inhibition also has other effects, including relaxation of airway smooth muscle, suppression of smooth muscle mitogenesis and modulation of excitatory activity in pulmonary nerves. Cilomilast is a systemically available, second-generation, selective PDE IV inhibitor. It retains the therapeutic activity of the first-generation PDE IV inhibitors but lacks their profound emetic effect. Cilomilast is the first drug to demonstrate a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with stable COPD. Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism. It exhibits linear pharmacokinetics, with low between-subject variability. Cilomilast is highly protein bound (99.4%), but this binding is concentration-independent at clinically relevant doses, and it has a small volume of distribution at steady state (17L). Plasma clearance (approximately 2 L/h) is almost entirely metabolic, through multiple parallel pathways. Its terminal elimination half-life is approximately 6.5 hours and steady state is rapidly achieved with twice-daily administration. The most abundant metabolite, formed by the action of cytochrome P450 2C8, has <10% of the activity of the parent molecule. Cilomilast pharmacokinetics in COPD patients were consistent with those in healthy subjects. Smoking, age and ethnicity had no clinically relevant effects. Total plasma cilomilast pharmacokinetic parameters did not change significantly with renal or hepatic impairment, but concentrations of unbound cilomilast increased with declining renal or hepatic function. Cilomilast had no clinically relevant interactions with a range of drugs likely to be coadministered to patients with COPD, with the exception of erythromycin where concurrent administration with cilomilast was associated with an increased incidence of gastrointestinal adverse events, a pharmacodynamic interaction predicted by their secondary pharmacology. Nausea was the principal adverse reaction seen in healthy subjects taking cilomilast, but this was reduced by administration with food or by use of simple dose-escalation regimens. Cilomilast has not shown a propensity for any of the serious cardiac or neurological adverse effects associated with theophylline. Cilomilast exhibits favourable and predictable pharmacokinetics, has few clinically relevant drug-drug interactions and has demonstrated effects on measures of inflammation of potential benefit in the treatment of COPD. It is generally well tolerated and has not generated safety concerns in any clinical study.
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PMID:Clinical pharmacology of Cilomilast. 1650 57

The central role of cyclic nucleotides as intracellular second messengers dates back almost 50 years. The importance of phosphodiesterase in regulating this system was recognized early, and the potential therapeutic role of phosphodiesterase inhibitors in modulating pathologic conditions was also suggested. At that time, the methylxanthines represented major pharmacologic agents capable of inhibiting cyclic nucleotides and were widely used in respiratory medicine. Initially, bronchodilator effects were considered their major mechanism of action, but subsequent studies suggested other potential roles including an anti-inflammatory one. A number of developments led to the decline in popularity of this class of agents, the foremost being their side-effect profile. The discovery of multiple phosphodiesterase isoforms paired with a better understanding of the physiologic and clinical properties of the phosphodiesterases has re-awakened interest in therapeutic agents in this area and in particular the potential for the development of selective phosphodiesterase inhibitors. Cilomilast is a systemically available, second- generation, selective phosphodiesterase-4 inhibitor. It retains the therapeutic activity of the first generation phosphodiesterase-4 inhibitors (such as rolipram) but is believed to have less of an emetic effect. Cilomilast causes a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease is now considered a chronic inflammatory disease of the lungs resulting from prolonged exposure to inflammatory agents in cigarette smoke and other environmental and occupational pollutants, and it is currently the principal target of cilomilast. It is characterized by progressive destruction of parenchymal tissue and punctuated by acute exacerbations. The inflammation is thought to begin in the peripheral airways and lung parenchyma. Chronic obstructive pulmonary disease is a progressive disease, leading to disability and eventual death despite conventional therapy. Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism. It exhibits low between-subject variability. Cilomilast is predominantly protein bound. Plasma clearance is almost entirely metabolic, through multiple parallel pathways. Its terminal elimination half-life is approximately 6.5 hours, and steady state is rapidly achieved. A dose of 15 mg twice daily has been found to be clinically effective. Smoking and age have no clinically relevant effects on cilomilast pharmacokinetics. Most drugs frequently used in patients with chronic obstructive pulmonary disease do not alter its side effect profile. Initial concerns of arteritis involving the gastrointestinal tract in rodent animal models have not been reported in clinical trials. Nausea, presumably of central origin, is the principal adverse reaction seen in healthy subjects taking cilomilast. It has not been associated with the serious cardiac or neurological adverse effects seen with theophylline. Preliminary clinical studies suggest a favorable clinical effect in chronic obstructive pulmonary disease. Cilomilast is generally well tolerated and has not generated safety concerns in reported clinical studies.
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PMID:Cilomilast. 1670 20

A 78-year-old man with severe chronic obstructive pulmonary disease presented to our pain medicine clinic for treatment of post herpetic neuralgia. Pharmacotherapy with tricyclic antidepressants, anticonvulsants, tramadol and traditional analgesics had failed, primarily due to adverse drug effects, particularly sedation, dizziness and nausea. Consequently, intravenous salmon calcitonin was administered, based on evidence of efficacy in the treatment of other neuropathic pain syndromes and its relatively benign side-effects profile. The patient reported immediate and sustained improvement in his post herpetic neuralgia for over two months, without adverse effects from the calcitonin therapy.
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PMID:Salmon calcitonin in the treatment of post herpetic neuralgia. 1706 47

Chronic obstructive pulmonary disease is characterized by a rapid decline in lung function due to small airway fibrosis, mucus hypersecretion and emphysema. The major causative factor for COPD is cigarette smoking that drives an inflammatory process that gives rise to leukocyte recruitment, imbalance in protease levels and consequently matrix remodeling resulting in small airway fibrosis and loss of alveolar tissue. Current drug treatment improves symptoms but do not alter the underlying progression of this disease. The failure of antiinflammatory drugs like glucocorticosteroids to have a major impact in this disease has hastened the need to develop novel therapeutic strategies. Phosphodiesterase (PDE) 4 inhibitors are novel anti-inflammatory drugs that have recently been show to document clinical efficacy in this disease, although their utility is hampered by class related side-effects of nausea, emesis and diarrhea. Whilst it is not yet clear whether such drugs will prevent emphysema, this is a distinct possibility provided experimental observations from preclinical studies translate to man. This review will discuss the current standing of PDE4 inhibitors like roflumilast as novel treatments for COPD and the potential for developing nonemetic anti-inflammatory drugs.
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PMID:PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast. 1804 84

Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting beta2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5 min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3 L, 44% predicted) received nebulized formoterol fumarate (Perforomist inhalation solution; FFIS 20 microg) or DPI (Foradil Aerolizer; FA 12 microg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George's Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0-12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0-12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, -4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency > or = 1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI.
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PMID:Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients. 1836 1

Phosphodiesterase4 inhibitors are currently under development for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease. The rationale for the development of this drug class stems from our understanding of the role of PDE4 in suppressing the function of a range of inflammatory and resident cells thought to contribute toward the pathogenesis of these diseases. Similarly, numerous preclinical in vivo studies have shown that PDE4 inhibitors suppress characteristic features of these diseases, namely, cell recruitment, activation of inflammatory cells and physiological changes in lung function in response to a range of insults to the airways. These potentially beneficial actions of PDE4 inhibitors have been successfully translated in phase II and III clinical trials with roflumilast and cilomilast. However, dose limiting side effects of nausea, diarrhoea and headache have tempered the enthusiasm of this drug class for the treatment of these respiratory diseases. A number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects, including delivery via the inhaled route, and/or development of non-emetic PDE4 inhibitors and mixed PDE inhibitors.
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PMID:PDE4 inhibitors: current status. 1866 Aug 25

Healthy donors (HDs) who were mobilized using lenograstim (LENO) and who were undergoing peripheral haematopoietic progenitor cell collection with apheresis (HPC-A) were enrolled in a surveillance protocol. In all, 184 HDs have been assessed with a median follow-up of 62 months (range 2-155). HDs received LENO at a median dose of 10 microg/kg (range 5-15). Bone pain was reported as the most frequent short-term adverse event (71.2%). Other commonly observed short-term symptoms included fatigue (19.0%), fever (5.4%), headache (27.7%), nausea (12.0%) and insomnia (22.3%). Spleen size increased in 4.3% of the donors. No vascular disorders or cardiac disease occurred. Long-term follow-up included monitoring of adverse events, neoplastic disease or other pathologies. Transit ischaemic attack occurred in one donor (39 months post-donation). One autoimmune event was reported at 28 months post-recombinant human granulocyte (rhG)-CSF (ankylosing spondylitis); one donor with a history of chronic obstructive pulmonary disease developed secondary polyglobulia (50 months post-rhG-CSF). One donor was diagnosed with lung cancer at 19 months post-donation. No haematological disease was observed. In conclusion, the short-term safety appears to be verified, whereas, although the study identified no increased risks of malignancy among HDs who received rhG-CSF, long-term safety requires more complete data sets, especially a longer follow-up and a larger number of HDs.
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PMID:Short and long-term safety of lenograstim administration in healthy peripheral haematopoietic progenitor cell donors: a single centre experience. 1918 33


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