piperidines and Pulmonary-Edema

At least four doses of quinine followed by a single dose of mefloquine or by a single dose of sulfadoxine-pyrimethamine are two highly effective regimens for chloroquine-resistant falciparum malaria. Mefloquine alone is valuable in ambulant patients. Chloroquine-sensitive falciparum malaria can be treated with a course of chloroquine. Vivax and all other types of malaria should be treated with sequential chloroquine and primaquine. Quinine, by intravenous infusion, is the most effective drug for severe falciparum malaria. The optimum intravenous dose varies between 5 mg/kg and 10 mg/kg administered over four hours. Intravenous or oral quinine should be administered about every 12 hours and the total daily dose of quinine should rarely exceed 20 mg/kg. Intravenous fluid input should be controlled in falciparum malaria to prevent pulmonary oedema. Established renal failure is best treated by dialysis. The value of adrenocortical steroids for falciparum coma has not been established. Fresh blood transfusion may be helpful in small doses for severe anaemia and to replace clotting factors. Anticoagulants, such as heparin, should not be used in falciparum malaria.

Topics: Anemia; Antimalarials; Blackwater Fever; Child; Child, Preschool; Chloroquine; Coma; Drug Combinations; Drug Resistance, Microbial; Hemorrhage; Humans; Kidney Failure, Chronic; Malaria; Piperidines; Plasmodium falciparum; Plasmodium vivax; Primaquine; Pulmonary Edema; Quinine; Quinolines; Sulfadoxine

The anaplastic lymphoma kinase (ALK) inhibitor alectinib is recommended as a first-line treatment for ALK lung cancer. Interstitial lung disease is the most common adverse event leading to discontinuation of alectinib. The purpose of this study was to use the Japanese Adverse Drug Event Report database for the evaluation of incidence trends and timing of alectinib toxicity in the lungs.. Adverse drug reactions (ADRs) by alectinib were extracted between April 2004 and March 2021. Data related to lung toxicity ADRs were analyzed, and the relative risk was estimated using the reporting odds ratio (ROR) and 95% confidence interval (CI). The time of onset of the lung toxicity signs was noted.. We obtained 524 reports of ADRs associated with alectinib. Of these, 157 were lung toxicity, including interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema. The RORs for these signs were 10.28 (95%CI=8.38-12.60), 9.19 (5.58-15.13), 7.40 (3.67-14.88), and 7.01 (3.13-15.69), respectively. The median onset times (quartiles, 25-75%) of interstitial lung disease, lung disorder, pneumonitis, and pulmonary edema associated with alectinib treatment were 92 (36-195), 57 (51-129), 228 (62-431), and 83 (22-96) days, respectively.. Among the lung toxicity signs, interstitial lung disease had the highest ROR, suggesting a strong causal relationship with alectinib treatment. Interstitial lung disease most frequently developed within 60 days after the start of treatment. These results will be useful for monitoring adverse events associated with the use of alectinib.

Topics: Adverse Drug Reaction Reporting Systems; Carbazoles; Humans; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Pharmacovigilance; Piperidines; Protein Kinase Inhibitors; Pulmonary Edema; Receptor Protein-Tyrosine Kinases

Heatstroke is still a potentially fatal threat during summer heat waves, despite improved prevention and treatment. It is reported that the transient receptor potential vanilloid 4 (TRPV4) inhibitor may protect septicemia mice. Many aspects of heatstroke have been defined, from the sepsis-mimic inflammatory response to hyperthermia. Hence, TRPV4 may be a therapeutic target for heatstroke. The results in murine models of heatstroke verified that GSK2193874, as a selected TRPV4 inhibitor, was injected at heatstroke onset, and then reduced the reduction of core temperature, the death rate, wet/dry ratio of the lung, levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, coagulation indicators, the degree of organ injury, and caspase-3/7 activity (P<0.05). But GSK2193874 treatment before heat stress did not improve the symptoms of heatstroke mice. Therefore, TRPV4 should be involved in heatstroke-induced injury. Timely GSK2193874 administration may be useful to reduce heatstroke-induced injury. TRPV4 may be a potential new therapeutic target in fatal heatstroke.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Caspase 3; Caspase 7; Disease Models, Animal; Heat Stroke; Hot Temperature; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Piperidines; Pulmonary Edema; Quinolines; TRPV Cation Channels; Tumor Necrosis Factor-alpha

Piperine, one of the active components of black pepper, has been reported to have antioxidant and anti-inflammatory activities. However, the effects of piperine on lipolysaccharide (LPS)-induced acute lung injury (ALI) have not been reported. Thus, the protective effects of piperine against LPS-induced ALI were investigated in this study. LPS-induced lung injury was assessed by histological study, myeloperoxidase (MPO) activity, and inflammatory cytokine production. Our results demonstrated that piperine attenuated LPS-induced MPO activity, lung edema, and inflammatory cytokines TNF-α, IL-6, and IL-1β production. Histological studies showed that piperine obviously attenuated LPS-induced lung injury. In addition, piperine significantly inhibited LPS-induced NF-κB activation. In conclusion, our results demonstrated that piperine had a protective effect on LPS-induced ALI. The anti-inflammatory mechanism of piperine is through inhibition of NF-κB activation. Piperine may be a potential therapeutic agent for ALI.

Topics: Acute Lung Injury; Alkaloids; Animals; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Enzyme Activation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung Injury; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; NF-kappa B; Peroxidase; Piperidines; Polyunsaturated Alkamides; Pulmonary Edema; Signal Transduction; Tumor Necrosis Factor-alpha

Lung injury and respiratory distress syndrome are frequent symptoms observed in the most severe cases of scorpion envenomation. The uncontrolled transmigration of leukocyte cells into the lung interstitium and alveolar space and pulmonary edema may be the cause of death. Mast cells can release various inflammatory mediators known to be involved in the development of lung edema following scorpion venom injection. The present study was designed to determine the evidence of neurokinin 1 (NK1) receptor and the involvement of mast cell activation to induce pulmonary edema and to increase vascular permeability after Androctonus australis hector (Aah) venom administration. To this end, mast cells were depleted using compound 48/80 (C48/80). Furthermore, the involvement of tachykinin NK1 receptors expressed on mast cell membranes was elucidated by their blocking with an antagonist. On the other hand, the ability of Aah venom to increase vascular permeability and to induce edema was also assessed by measuring the amount of Evans blue dye (EBD) extravasation in bronchoalveolar lavage (BAL) fluid and in the lungs of mice. Pulmonary edema, as assessed by the levels of EBD extravasation, was completely inhibited in compound 48/80-treated animals. Depletion by stimuli non-immunological C48/80 component markedly reduced induced inflammatory response following the venom administration. The mast cells seem to play an important role in the development of lung injury and the increase of vascular permeability in mice following the subcutaneous administration of Aah scorpion venom through the NK1 receptor.

Topics: Acute Lung Injury; Animals; Bronchial Hyperreactivity; Capillary Permeability; Cell Degranulation; Humans; Indoles; Male; Mast Cells; Mice; Mice, Inbred Strains; Neurokinin-1 Receptor Antagonists; Piperidines; Pulmonary Edema; Receptors, Neurokinin-1; Scorpion Stings; Scorpion Venoms; Scorpions; Tachykinins

We investigated the role of intracerebroventricular (ICV) injection of rimonabant (500ng), a CB1 antagonist, on lipopolysaccharide ((LPS) 5mg/kg)-induced pulmonary inflammation in rats in an isolated perfused lung model. There were decreases in pulmonary capillary pressure (Ppc) and increases in the ((Wet-Dry)/Dry lung weight)/(Ppc) ratio in the ICV-vehicle/LPS group at 4h. There were decreases in TLR4 pathway markers, such as interleukin receptor-associated kinase-1, IκBα, Raf1 and phospho-SFK (Tyr416) at 30min and at 4h increases in IL-6, vascular cell adhesion molecule-1 and myeloperoxidase in lung homogenate. Intracerebroventricular rimonabant attenuated these LPS-induced responses, indicating that ICV rimonabant modulates LPS-initiated pulmonary inflammation.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Injections, Intraventricular; Lipopolysaccharides; Lung; Male; Peroxidase; Piperidines; Pneumonia; Pulmonary Edema; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Signal Transduction; Time Factors; Toll-Like Receptor 4

Role of 2-Deoxy-D-glucose (2-DG) in reversing the Indian red scorpion (Mesobuthus tamulus concanesis Pocock, MBT) venom-induced toxicity was examined. Femoral arterial pressure, ECG and respiratory movements were recorded in urethane anesthetized rats. Plasma glucose and serum insulin levels were also estimated. Intravenous injection of 5 mg/kg MBT venom produced immediate decrease in mean arterial pressure, heart rate and respiratory frequency followed by an increase and subsequent progressive decrease. ECG pattern exhibited ischaemic changes. There was hyperinsulinemia after venom without corresponding decrease in plasma glucose. The animals died within 37 +/- 9 min and demonstrated significant increase in pulmonary water content. 2-DG pretreatment (0.5 g/kg, iv) improved the cardiopulmonary abnormalities induced by venom and the animals survived for nearly 120 min. There was no hyperinsulinemia and increased pulmonary water content in these animals. In insulin (2 IU/kg) treated rats, the MBT venom-induced cardiopulmonary abnormalities were attenuated and ECG abnormalities were reversed. The pulmonary water content in these animals exhibited a decreasing trend and the animals survived for 120 min. Repaglinide (10 microg/kg, iv) pretreatment failed to reverse the venom-induced cardiopulmonary changes including the increased pulmonary water content. The survival time was similar to venom only group. The present results reveal that 2-DG reverses the venom-induced cardiopulmonary toxicity probably by restoring insulin sensitivity.

Topics: Anesthesia; Animals; Blood Glucose; Carbamates; Cardiovascular Abnormalities; Deoxyglucose; Hyperglycemia; India; Insulin; Lung Diseases; Myocardial Ischemia; Piperidines; Pulmonary Edema; Rats; Respiration; Scorpion Venoms; Ultrasonography

Valvular heart diseases have adverse effects on hemodynamic condition in the parturients during pregnancy. Cesarean section with an opioid based general anesthesia has been used to alleviate these deleterious effects. We hereby describe the effective application of remifentanil, for cesarean section under general anesthesia, in a 30 yr. old primigravida suffering of severe multivalvular heart disease and pulmonary hypertension presenting with pulmonary edema who was in active labor and without neonatal respiratory depression.

Topics: Adult; Anesthesia, General; Anesthesia, Obstetrical; Anesthetics, Intravenous; Cesarean Section; Female; Humans; Mitral Valve Stenosis; Piperidines; Pregnancy; Pregnancy Complications, Cardiovascular; Pulmonary Edema; Remifentanil; Severity of Illness Index

Adenosine and the activation of specific adenosine receptors are implicated in the attenuation of inflammation and organ ischemia-reperfusion injury. We hypothesized that activation of A(1), A(2A), or A(3) adenosine receptors would provide protection against lung ischemia-reperfusion injury.. With the use of an isolated, ventilated, blood-perfused rabbit lung model, lungs underwent 18 hours of cold ischemia followed by 2 hours of reperfusion. Lungs were administered vehicle, adenosine, or selective A(1), A(2A), or A(3) receptor agonists (CCPA, ATL-313, or IB-MECA, respectively) alone or with their respective antagonists (DPCPX, ZM241385, or MRS1191) during reperfusion.. Compared with the vehicle-treated control group, treatment with A(1), A(2A), or A(3) agonists significantly improved function (increased lung compliance and oxygenation and decreased pulmonary artery pressure), decreased neutrophil infiltration by myeloperoxidase activity, decreased edema, and reduced tumor necrosis factor-alpha production. Adenosine treatment was also protective, but not to the level of the agonists. When each agonist was paired with its respective antagonist, all protective effects were blocked. The A(2A) agonist reduced pulmonary artery pressure and myeloperoxidase activity and increased oxygenation to a greater degree than the A(1) or A(3) agonists.. Selective activation of A(1), A(2A), or A(3) adenosine receptors provides significant protection against lung ischemia-reperfusion injury. The decreased elaboration of the potent proinflammatory cytokine tumor necrosis factor-alpha and decreased neutrophil sequestration likely contribute to the overall improvement in pulmonary function. These results provide evidence for the therapeutic potential of specific adenosine receptor agonists in lung transplant recipients.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Adenosine A3 Receptor Agonists; Adenosine A3 Receptor Antagonists; Animals; Blood Pressure; Disease Models, Animal; In Vitro Techniques; Lung; Lung Compliance; Lung Diseases; Perfusion; Peroxidase; Piperidines; Protective Agents; Pulmonary Artery; Pulmonary Edema; Rabbits; Receptor, Adenosine A1; Receptor, Adenosine A2A; Receptor, Adenosine A3; Reperfusion Injury; Tumor Necrosis Factor-alpha

A 54-year-old man had emergency laparoscopic chelecystectomy for acute cholecystitis. General inflammatory change (CRP 26.6 mg x dl(-1), WBC 26,800) was noted preoperatively. Anesthesia was induced with propofol and remifentanil and maintained with sevoflurane in oxygen and remifentanil. Operation was performed uneventfully within 128 min. At the end of the surgery, 0.1 mg of fentanyl was administrated. After confirming adequate respiration and oxygenation, endotracheal tube was removed. At that period, hypertension (SBP 220 mmHg) and tachycardia (HR 122 beats x min(-1)) developed. Soon thereafter, he became agitated and complained of dyspnea with desaturation (Spo2 < 70%). After reintubation, massive pinkish babbly secretion flowed out from the endotracheal tube. Chest X-ray revealed diffuse bilateral infiltration of the lungs without cardiomegaly. He was transferred to the intensive care unit for mechanical ventilation. His condition improved progressively and was extubated on the POD 6. The cause of pulmonary edema is thought to be profound centralization of circulating volume associated with catecholamine-induced vasoconstriction due to rapid disappearance of remifentanil effect. Adequate analgesia is necessary during remifentanil-based anesthesia especially in patients suffering from general inflammatory changes.

Topics: Aged; Anesthesia; Anesthesia Recovery Period; Cholecystectomy, Laparoscopic; Cholecystitis, Acute; Humans; Hypertension; Intubation, Intratracheal; Male; Perioperative Care; Piperidines; Postoperative Complications; Pulmonary Edema; Remifentanil

Endothelin-1 (ET-1) is thought to play a pivotal role in pulmonary edema formation. The underlying mechanisms remain uncertain but may include alterations in capillary pressure and vascular permeability. There are no studies investigating whether ET-1 also affects alveolar fluid clearance which is the primary mechanism for the resolution of pulmonary edema. Therefore, we performed this study to clarify effects of ET-1 on alveolar reabsorption and fluid balance in the rat lung.. Alveolar fluid clearance was measured in fluid instilled rat lungs using a 5% albumin solution with or without ET-1 (10(-7) M) and/or amiloride (100 microM). Net alveolar fluid balance, time course of edema formation, pulmonary capillary pressure, and alveolar permeability to albumin were measured in the isolated, ventilated, constant pressure perfused rat lung with or without ET-1 (0.8 nM) added to the perfusate.. In the fluid-instilled lung, ET-1 reduced alveolar fluid clearance by about 65%, an effect that was related to a decrease in amiloride-sensitive transepithelial Na(+) transport (P < 0.001). The ET-1-induced inhibition was completely prevented by the endothelin B receptor antagonist BQ788 (P = 0.006), whereas the endothelin A receptor antagonist BQ123 had no effect (P = 0.663). In the isolated, ventilated, perfused rat lung ET-1 caused a net accumulation of alveolar fluid by about 20% (P = 0.011 vs control), whereas lungs of control rats cleared about 20% of the instilled fluid. ET-1 increased pulmonary capillary pressure (+9.4 cm H(2)O), decreased perfusate flow (-81%), accelerated lung weight gain and reduced lung survival time (P < 0.001). Permeability to albumin was not significantly affected by ET-1 (P = 0.24).. ET-1 inhibits alveolar fluid clearance of anesthetized rats by inhibition of amiloride-sensitive epithelial Na(+) channels. The inhibitory effect of ET-1 results from activation of the endothelin B receptor. These findings suggest a mechanism by which ET-1, in addition to increasing capillary pressure, contributes to pulmonary edema formation.

Topics: Albumins; Amiloride; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Capillaries; Capillary Permeability; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epithelial Sodium Channel Blockers; Epithelial Sodium Channels; Extravascular Lung Water; Hydrostatic Pressure; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Alveoli; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sodium Channel Blockers; Time Factors; Vasoconstriction

The Tako-Tsubo syndrome (or transient left ventricular apical balloning) is a new clinical entity, very similar to acute myocardial infarction, but different by its excellent short-term prognosis. It has been reported after a physical or an emotional stress, and it is diagnosed by a coronary angiogram and a left ventriculography. We report here a case of Tako-Tsubo syndrome related to an anaphylactic shock caused by succinylcholine during general anaesthesia of a female patient, wearing an unadjustable gastric band.

Topics: Anaphylaxis; Anesthesia, General; Anesthesia, Intravenous; Diabetes Mellitus, Type 2; Female; Gastroplasty; Heart Arrest; Humans; Intraoperative Complications; Laparoscopy; Middle Aged; Neuromuscular Depolarizing Agents; Obesity; Pelvic Floor; Piperidines; Postoperative Complications; Propofol; Pulmonary Edema; Remifentanil; Succinylcholine; Takotsubo Cardiomyopathy; Ventricular Fibrillation

Endothelin 1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonism of the ET-1-mediated effects has become an important therapeutic approach. ET-1 (A and B) receptors are differentially distributed in the lung vasculature. Whereas the ET(A) receptors mainly mediate vasoconstriction, the endothelial ET(B) receptor seems to have vasodilative properties. We sought to determine if antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET-1-mediated pulmonary hypertension.

Topics: Administration, Inhalation; Antihypertensive Agents; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Artery; Pulmonary Edema; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Cannabinoids have been shown to inhibit sensory nerve activation in guinea-pigs and humans. Their effects are mediated by specific activation of two types of receptors, named CB(1) and CB(2). The purpose of this study was to investigate the effects of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone, a non selective agonist of cannabinoid receptors, and JWH 133, (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran a selective cannabinoid CB(2) receptor agonist, on the sensory nerve component of intraoesophageal (i.oe.) HCl-induced airway microvascular leakage and bronchoconstriction in guinea-pigs. We also tested the effect of WIN 55,212-2 on substance P-induced plasma extravasation and bronchoconstriction. Airway microvascular leakage and bronchoconstriction induced by i.oe. HCl was inhibited by the cannabinoid CB(1)/CB(2) agonist WIN 55,212-2 (0.3-3 mg/kg i.p.) in a dose-dependent manner (maximal inhibition at the dose of 3 mg kg(-1), P<0.01). The effect of WIN 55,212-2 was inhibited by a cannabinoid CB(2) receptor antagonist SR 144528, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1] heptan-2yl]-5-(-4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide], but not by a CB(1) receptor antagonist, SR 141716, [N-(piperidin-1yl)-5-(-4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride]. The cannabinoid CB(2) agonist JWH 133 (0.3-3 mg/kg i.p.) mimicked the inhibitory effect of WIN 55,212-2 on HCl-induced microvascular leakage. Under similar conditions, WIN 55,212-2 (1 mg kg (-1) i.p.) was unable to counteract the airway microvascular leakage and bronchoconstriction induced by substance P. These results suggest that inhibition by WIN 55,212-2 of airway plasma extravasation and bronchoconstriction induced by i.oe. HCl instillation in guinea-pigs is mediated through cannabinoid CB(2) receptor activation.

Topics: Airway Obstruction; Animals; Benzoxazines; Bronchi; Bronchoconstriction; Camphanes; Cannabinoids; Capillary Permeability; Disease Models, Animal; Dose-Response Relationship, Drug; Esophagus; Extravasation of Diagnostic and Therapeutic Materials; Gastroesophageal Reflux; Guinea Pigs; Hydrochloric Acid; Male; Morpholines; Naphthalenes; Piperidines; Pulmonary Edema; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Respiratory Function Tests; Rimonabant; Trachea

Topics: Anesthesia, Intravenous; Anesthesia, Local; Anesthetics, Intravenous; Conscious Sedation; Female; Fetofetal Transfusion; Humans; Laparoscopy; Laser Coagulation; Piperidines; Pregnancy; Pulmonary Edema; Remifentanil; Retrospective Studies; Twins, Monozygotic

The tachykinin neurokinin B (NKB) has been implicated in the hypertension that characterises pre-eclampsia, a condition where tissue oedema is also observed. The ability of NKB, administered intradermally or intravenously, to induce oedema formation (assessed as plasma extravasation) was examined by extravascular accumulation of intravenously injected (125)I-albumin in wild-type and tachykinin NK(1) receptor knockout mice. Intradermal NKB (30-300 pmol) caused dose-dependent plasma extravasation in wild-type (P < 0.05) but not NK(1) knockout mice, indicating an essential role for the NK(1) receptor in mediating NKB-induced skin oedema. Intravenous administration of NKB to wild-type mice produced plasma extravasation in skin, uterus, liver (P < 0.05) and particularly in the lung (P < 0.01). Surprisingly, the same doses of NKB led to plasma extravasation in the lung and liver of NK(1) knockout mice. By comparison, the tachykinin substance P induced only minimal plasma extravasation in the lungs of wild-type mice. The plasma extravasation produced by NKB in the lungs of NK(1) receptor knockout mice was unaffected by treatment with the NK(2) receptor antagonist SR48968 (3 mg kg(-1)), by the NK(3) receptor antagonists SR142801 (3 mg kg(-1)) and SB-222200 (5 mg kg(-1)) or by the cyclo-oxygenase (COX) inhibitor indomethacin (20 mg kg(-1)). L-Nitro-arginine methyl ester (15 mg kg(-1)), an inhibitor of endothelial nitric oxide synthase (eNOS), produced only a partial inhibition. We conclude that NKB is a potent stimulator of plasma extravasation through two distinct pathways: via activation of NK(1) receptors, and via a novel neurokinin receptor-independent pathway specific to NKB that operates in the mouse lung. These findings are in keeping with a role for NKB in mediating plasma extravasation in diseases such as pre-eclampsia.

Topics: Animals; Antipsychotic Agents; Benzamides; Cyclooxygenase Inhibitors; Edema; Enzyme Inhibitors; Extravascular Lung Water; Female; Indomethacin; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurokinin B; Neurokinin-1 Receptor Antagonists; NG-Nitroarginine Methyl Ester; Piperidines; Plasma; Pulmonary Edema; Receptors, Neurokinin-1; Substance P

Release of human lung mast cell tryptase may be important in the pathophysiology of asthma. We examined the effect of the reversible, nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and hyper-reactivity in a murine model of asthma. MOL 6131 is a potent selective nonpeptide inhibitor of human lung mast cell tryptase based upon a beta-strand template (K(i) = 45 nM) that does not inhibit trypsin (K(i) = 1,061 nM), thrombin (K(i) = 23, 640 nM), or other serine proteases. BALB/c mice after i.p. OVA sensitization (day 0) were challenged intratracheally with OVA on days 8, 15, 18, and 21. MOL 6131, administered days 18-21, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL 6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia, mucus secretion, and peribronchial edema and also inhibited the release of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase inhibition did not alter airway hyper-reactivity to methacholine in vivo. These results support tryptase as a therapeutic target in asthma and indicate that selective tryptase inhibitors can reduce allergic airway inflammation.

Topics: Animals; Asthma; Bridged Bicyclo Compounds, Heterocyclic; Bronchial Diseases; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Movement; Cytokines; Eosinophils; Humans; Inflammation; Lung; Mice; Mice, Inbred BALB C; Models, Molecular; Mucus; Ovalbumin; Piperidines; Pulmonary Edema; Pulmonary Eosinophilia; Serine Endopeptidases; Serine Proteinase Inhibitors; Tryptases; Vascular Cell Adhesion Molecule-1

Remifentanil is a synthetic opiate with evident advantages for various anesthetic techniques, enhancing quality of anesthesia. Indications are increasingly well-defined. Remifentanil may be used in obstetric analgesia-anesthesia thanks to advantages demonstrated in patients with heart disease (cardiac and non-cardiac anesthesia) and in those requiring neuroanesthesia. Remifentanil is known to cross the placenta rapidly and to be rapidly metabolized and redistributed to both mother and fetus. Based on this, and on pharmacokinetic and pharmacodynamic studies in children, we judged remifentanil to be indicated for use in two patients undergoing emergency cesarean section, for whom hemodynamic stability and immediate postoperative assessment were basic requirements. The first case involved a woman 40 weeks pregnant with a history of mitral valve prolapse and an episode of acute pulmonary edema in the 28th week, who presented with ruptured membrane and the fetus in sacroposterior breech presentation without subsequent progression of labor. The second involved a woman 40-weeks pregnant with a diagnosis of Hunt-Hess grade II subarachnoid hemorrhage who had gone into labor. Outcome was satisfactory in both cases, with no complications potentially affecting the status of either mother or child. No infant respiratory insufficiency occurred and Apgar scores were favorable. We consider remifentanil to be safe and effective for general anesthesia for emergency cesarean delivery in patients with cardiac and/or neurological risk factors.

Topics: Adult; Anesthesia, General; Anesthesia, Obstetrical; Anesthetics, General; Apgar Score; Cesarean Section; Emergencies; Female; Humans; Infant, Newborn; Intracranial Aneurysm; Maternal-Fetal Exchange; Mitral Valve Prolapse; Obstetric Labor Complications; Piperidines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Pregnancy Outcome; Pulmonary Edema; Remifentanil; Subarachnoid Hemorrhage

Although prior studies suggest that hypoxia may increase pulmonary vascular permeability, the mechanisms responsible for that effect remain uncertain. Neprilysin (neutral endopeptidase) is a cell surface metallopeptidase that degrades several vasoactive peptides including substance P and bradykinin. We hypothesized that hypoxia could reduce lung neprilysin expression, leading to increased vascular leak. Weanling rats were exposed to normobaric hypoxia (inspired O(2) fraction = 0.1). Lung neprilysin activity was significantly decreased after 24 and 48 h of hypoxia (P < 0.006). The decrease in enzyme activity was associated with decreased lung neprilysin protein content and decreased lung neprilysin mRNA expression. Immunohistochemistry showed a predominantly perivascular distribution of neprilysin, with clear reductions in neprilysin immunoreactivity after exposure to hypoxia. Exposure to hypoxia for 24 h also caused marked increases in vascular leak (P = 0.008), which were reversed by the administration of recombinant neprilysin. The hypoxia-induced increase in leak was also reversed by substance P and bradykinin receptor antagonists. We conclude that in young rats hypoxia decreases lung neprilysin expression, which contributes to increased pulmonary vascular leak via substance P and bradykinin receptors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Gene Expression Regulation, Enzymologic; Hypoxia; Lung; Male; Methionine; Microcirculation; Neprilysin; Neurokinin-1 Receptor Antagonists; Oxygen; Piperidines; Protease Inhibitors; Pulmonary Edema; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; RNA, Messenger; Specific Pathogen-Free Organisms; Substance P; Water

The pharmacological mechanisms involved in the acetylcholine (ACh)- and substance P (SP)-induced changes in pulmonary mechanics were studied in isolated perfused rabbit lungs. Tracheal pressure (Ptr) and airflow were measured by a Fleisch pneumotachograph and pressure transducers. Air volume, lung resistance (RL) and dynamic compliance (Cdyn) were calculated. ACh induced a dose-dependent increase in Ptr and RL, and a decrease in Cdyn. These effects were strongly prevented by atropine, and partly by SR140333, a neurokinin NK1 receptor antagonist; SR48968, a neurokinin NK2 receptor antagonist; indomethacin and antihistaminics. Ketanserin had no significant protective effect against ACh. SP also induced concentration-dependent increases in RL and decreases in Cdyn. SR140333 and atropine strongly inhibited the effects of SP, while ketanserin, SR48968, antihistaminics and indomethacin did not protect the lungs against this drug. 5-hydroxytryptamine induced no significant change in lung mechanic parameters. Cumulative concentrations of histamine increased RL and decreased Cdyn. We conclude that ACh-induced changes in lung resistance and compliance are in part mediated by a direct effect on airway smooth muscle and in part by the stimulation of C fibers, by the release of histamine from mast cells and by the synthesis of arachidonic acid metabolites. In turn, the effects of SP on lung mechanics are partly due to cholinergic activation.

Topics: Acetylcholine; Analysis of Variance; Animals; Benzamides; Dose-Response Relationship, Drug; Female; Histamine; Lung; Male; Muscle, Smooth; Perfusion; Piperidines; Pulmonary Circulation; Pulmonary Edema; Quinuclidines; Rabbits; Substance P; Vasoconstriction

The modulatory role of histamine H3 receptors in pulmonary oedema induced by acetylcholine, capsaicin and by exogenous substance P was investigated in isolated, ventilated rabbit lungs. Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). Acetylcholine (10(-8) to 10(-4) M), substance P (10(-10) to 10(-6) M), capsaicin (10(-4) M) and 5-hydroxytryptamine (5-HT) (10(-4) M) induced an increase in the Kf,c. Carboperamide, a novel histamine H3 receptor antagonist, induced a significant leftward shift of the concentration-response curve to acetylcholine and also enhanced the effect of capsaicin on the Kf,c, while it had no significant effect on the response to substance P and 5-HT. Imetit, a new histamine H3 receptor agonist, strongly inhibited the effects of acetylcholine and capsaicin. Imetit also strongly protected the lung against substance P effects but did not prevent the 5-HT-induced increase in the Kf,c. Carboperamide completely blocked the inhibitory effect of Imetit on the acetylcholine response. (R)-alpha-Methylhistamine, an other histamine H3 receptor agonist, had the same protective effect against acetylcholine response as Imetit. We conclude that histamine H3 receptors could protect the lung against acetylcholine- and capsaicin-induced oedema via a prejunctional modulatory effect on the C-fibres. However, since the response to exogenous substance P was also inhibited by histamine H3 receptor stimulation, the presence of such receptors at a postsynaptic level, probably on mast cells, was also suggested.

Topics: Acetylcholine; Animals; Capillary Permeability; Capsaicin; Dose-Response Relationship, Drug; Drug Interactions; Endothelium; Female; Histamine Agonists; Histamine Antagonists; Imidazoles; In Vitro Techniques; Lung; Male; Nerve Fibers; Piperidines; Pulmonary Edema; Rabbits; Receptors, Histamine H3; Serotonin; Substance P; Thiourea

Topics: Acute Disease; Adult; Aminopyrine; Benzophenones; Dipyrone; Drug Combinations; Drug Hypersensitivity; Humans; Male; Myocarditis; Piperidines; Pulmonary Edema

This study was performed to determine the cardiovascular and respiratory effects of ketanserin, a specific 5-HT2 antagonist, following oleic acid lung injury in anesthetized dogs. Following intravenous administration of oleic acid (0.1 ml/kg) to a control group (N = 7), systemic blood pressure decreased significantly. This lowered level of systemic blood pressure was maintained throughout the experiment. Cardiac output gradually decreased following oleic acid administration, while total peripheral resistance, pulmonary vascular resistance, and pulmonary arterial pressure were increased significantly. In a group treated with intravenous ketanserin (0.16 mg/kg, N = 7) 60 min after the injection of oleic acid, no decrease in cardiac output was seen. The increased total peripheral resistance, pulmonary vascular resistance, and pulmonary arterial pressure following injection of oleic acid also were returned toward preoleic acid levels. However systemic blood pressure showed no significant improvement after treatment with ketanserin nor did ketanserin protect against progressive hypoxemia following pulmonary injury with oleic acid. A progressive increase in hemoglobin concentration was seen after oleic acid in the control group. This recovered toward the preoleic acid level following treatment with ketanserin. The postmortem lung wet-dry weight ratio was significantly lower in the treated group compared with the control group. In conclusion, these data suggest that serotonin may have a role in including cardiopulmonary hemodynamic disturbances and in producing increases in extravascular lung water when pulmonary edema is induced by oleic acid injection in anesthetized dogs.

Topics: Animals; Blood Pressure; Carbon Dioxide; Cardiac Output; Dogs; Hemodynamics; Hydrogen-Ion Concentration; Ketanserin; Lung; Oleic Acid; Oleic Acids; Oxygen; Piperidines; Pulmonary Edema; Serotonin; Serotonin Antagonists; Vascular Resistance

alpha-Naphthylthiourea (ANTU) damages the pulmonary capillary endothelium producing a marked pulmonary edema. Since the pulmonary microvasculature regulates the circulating levels of serotonin (5-HT), the role of 5-HT in the pathophysiology of ANTU-induced pulmonary edema was examined. Mice treated with ANTU (10 mg/kg, ip) rapidly developed pulmonary edema which was maximal at 3 hr and was resolved by 12 hr. The lung content of both endogenous 5-HT and a tracer dose of 5-[3H]HT paralleled the time course of the development and resolution of the pulmonary edema. ANTU produced a significant thrombocytopenia (58 to 72%) at all time points, and an elevated platelet content of 5-HT and 5-[3H]HT during the resolution phase (6 to 12 hr). Drugs possessing select effects on 5-HT were shown to alter the edematogenic response to ANTU. Fluoxetine, a selective inhibitor of 5-HT uptake, potentiated the pulmonary edema, while clorgyline, an irreversible inhibitor of type A monoamine oxidase, was without effect. Reserpine which depletes 5-HT stores prevented both thrombocytopenia and pulmonary edema in response to ANTU. Reloading the lung and platelet 5-HT stores of reserpinized animals reestablished the normal response to ANTU. Pretreatment with the selective 5-HT2 receptor antagonist, ketanserin, prevented the thrombocytopenia, the increase in lung content of 5-HT and 5-[3H]HT, and prevented the edematogenic response to ANTU by 70%. These data indicate a major role for 5-HT in the pathophysiology of acute lung microvascular injury produced by ANTU.

Topics: Animals; Blood Platelets; Clorgyline; Drug Interactions; Fluoxetine; Ketanserin; Lung; Male; Mice; Piperidines; Pulmonary Edema; Reserpine; Serotonin; Serotonin Antagonists; Thiourea; Thrombocytopenia

Topics: Angiotensin II; Antihypertensive Agents; Electrocardiography; Ergoloid Mesylates; Ergotamine; Female; Heart Failure; Humans; Hypertension; Hypotension, Orthostatic; Methyldopa; Middle Aged; Norepinephrine; Phytotherapy; Piperidines; Plants, Medicinal; Pulmonary Edema; Rauwolfia; Sympatholytics