pyrimidinones and Chronic-Disease

Pemirolast is a new oral, nonbronchodilator antiallergy medication that is being evaluated for the therapy of asthma. In this multicenter, double-blind, randomized study, 96 patients with mild asthma received pemirolast, 50 mg (n = 34); pemirolast, 25 mg (n = 31); or placebo (n = 31) BID for 6 weeks. Patients were evaluated weekly at the research centers; they maintained daily symptom diaries and measured peak expiratory flow rates twice a day. Methacholine challenge was performed at the start and end of the study. Results with pemirolast, 50 mg BID, showed statistically significant decrease in nocturnal symptoms (P = .02), in composite symptom scores (P = .02) and in bronchodilator use (P = .05) when compared with placebo. There were no statistically significant differences between treatments in pulmonary function tests or in methacholine challenge sensitivity. Pemirolast, 25 mg BID, did not differ from placebo. There were no significant adverse effects. Pemirolast, 50 mg BID, demonstrated sufficient antiasthma activity to warrant further studies in patients with more severe asthma and with higher doses.

Topics: Administration, Oral; Adolescent; Adult; Aged; Asthma; Bronchial Spasm; Chronic Disease; Double-Blind Method; Forced Expiratory Volume; Histamine Antagonists; Humans; Middle Aged; Placebos; Pyridines; Pyrimidinones

The wingless/integrase-1 (WNT)/β-catenin signaling pathway is active in several chronic lung diseases including idiopathic pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease. Although this WNT/β-catenin pathway activity is associated with an increase in mucus cell frequency and a decrease in ciliated cell frequency, a cause and consequence relationship between signaling and cell frequency has not been established. We previously demonstrated that genetic stabilization of β-catenin inhibited differentiation of mouse bronchiolar tissue stem cells (TSC). This study determined the effect of β-catenin and its co-factors P300 (E1A-binding protein, 300 kDa) and cAMP response element binding (CREB)-binding protein (CBP) on human bronchial epithelial TSC differentiation to mucus and ciliated cells. We developed a modified air-liquid interface (ALI) culture system in which mucus and ciliated cell frequency is similar. These cultures were treated with the β-catenin agonist CHIR99021 (CHIR) and antagonists to β-catenin (XAV939), P300 (IQ1), and CBP (ICG001). We report that human TSC differentiation to mucus and ciliated cells can be divided into two stages, specification and commitment. CHIR treatment inhibited mucus and ciliated cell commitment while XAV939 treatment demonstrated that β-catenin was necessary for mucus and ciliated cell specification. Additional studies demonstrate that a β-catenin/P300 complex promotes mucus cell specification and that β-catenin interacts with either P300 or CBP to inhibit ciliated cell commitment. These data indicate that activation of β-catenin-dependent signaling in chronic lung disease leads to changes in mucus and ciliated cell frequency and that P300 and CBP tune the β-catenin signal to favor mucus cell differentiation. Stem Cells 2018;36:1905-12.

Topics: Adolescent; Adult; Animals; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Bronchi; Cell Differentiation; Cell Line, Tumor; Chronic Disease; E1A-Associated p300 Protein; Epithelial Cells; Heterocyclic Compounds, 3-Ring; Humans; Lung Diseases; Mice; Mice, Knockout; Middle Aged; Peptide Fragments; Pyridines; Pyrimidines; Pyrimidinones; Respiratory Mucosa; Sialoglycoproteins; Stem Cells; Young Adult

To evaluate the distribution of a daily phosphodiesterase type 5 inhibitor dose (mirodenafil) in rat plasma and bladder and prostate tissue in a model of atherosclerosis-induced chronic pelvic ischemia.. Thirty-two 18-week-old male Sprague Dawley rats were divided into two groups. Group I (n = 16) comprised a chronic pelvic ischemia model treated with mirodenafil and group II (n = 16) comprised a sham-operated model also treated with mirodenafil. The mirodenafil concentrations in each organ were measured at specific time points after 14 days of daily mirodenafil administration. The drug distribution ratio of group I to group II of each organ was measured, and the bladder tissue-to-plasma and prostate tissue-to-plasma ratios were calculated.. The mean drug concentration in the bladder of the rats in group I did not differ significantly from that of group II after mirodenafil administration. In the prostate, the mean drug concentration of group I was significantly higher than that of group II at 1 and 4 hours after drug administration. The drug concentration was higher in the bladder tissue than in the prostate tissue and the bladder tissue-to-plasma ratio was significantly higher than the prostate tissue-to-plasma ratio.. Our results suggest that mirodenafil levels might be sufficient in the target tissue after daily treatment in an ischemia-induced aging model. Considering the difficulties of tissue distribution study in human subjects, the results of this investigation provided meaningful evidence of the application of daily doses of mirodenafil for treating lower urinary tract symptoms in an aging population.

Topics: Animals; Chronic Disease; Disease Models, Animal; Ischemia; Male; Pelvis; Phosphodiesterase 5 Inhibitors; Prostate; Pyrimidinones; Rats; Rats, Sprague-Dawley; Sulfonamides; Tissue Distribution; Urinary Bladder

Venous blood draining from the left atrium (LA) flows into the coronary sinus (CS) through the Marshall vein which has no valvular apparatus, thus allowing LA retroperfusion if reflow in the right atrium is hindered. We investigated pharmacologic atrial defibrillation via the CS in dogs with chronic atrial fibrillation (AF). Chronic AF was induced by rapid atrial pacing for 4-16 weeks in 6 mongrel dogs. A 7F occlusion balloon catheter was introduced into the proximal CS. Boluses of low doses of the class Ic antiarrhythmic drug, pilsicainide (2, 4, 6, and 8 mg as needed) or class III antiarrhythmic drug, nifekalant (0.5, 1, 2, and 4 mg) were infused directly within 3-4 seconds at 10 minute intervals into the temporarily balloon occluded CS near its orifice. In 4 of the 5 dogs (balloon catheter could not be placed in the CS in 1 dog), the cumulative dose of 11.5 ± 7.4 mg of pilsicainide was effective in restoring sinus rhythm; the venous concentration of pilsicainide was 1.23 ± 0.79 µg/mL. A cumulative dose of 7.5 mg nifekalant restored sinus rhythm in only 1 of the 6 dogs. Our results in dogs with sustained AF indicate that delivery of a class Ic or III antiarrhythmic drug near the CS ostium via the temporarily occluded CS is feasible and effective for pharmacologic atrial defibrillation; however, the effect may be related to the elevation of the serum concentration of the drug to the therapeutic range rather than to the delivery method itself.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Balloon Occlusion; Cardiac Pacing, Artificial; Chronic Disease; Coronary Sinus; Dogs; Drug Delivery Systems; Injections, Intravenous; Lidocaine; Pyrimidinones; Treatment Outcome

Chronic liver disease is often found in HIV infected patients. LPV as first choice drug is often used over long time periods. TDM as a tool in patients care is important but the knowledge of LPV-plasma-levels in patients with chronic liver disease remain uncertain. With this retrosepective analysis we want to show if there are differences in LPV-plasma-levels between patients with and without chronic liver diseases over a long-time period. LPV-plasma-levels were analysed with an HPLC-based methode. The LPV-plasma-levels over the time course in patients with chronic liver disease (n = 30) and patients without liver disease (n = 38) was evaluated. Liver function tests, CD4-cell count and HI-viral load was also correlated with liver disease. The LPV plasma-levels of n = 450 samples from 30 patients with liver disease (Hepatitis B: n = 17, Hepatitis C: n = 16, Alcoholic liver disease: n = 7) were determined over 18.7 +/- 16,3 months (1 - 48.5 months). A median of 10 samples per patient was eligible (2 - 50 samples). There are no significant differences according to liver disease in LPV-plasma levels (mean Ctrough without: 5917 +/- 4811 ng/ml, mean Ctrough with liver-disease: 6564 +/- 4517 ng/ml, p > 0.05). The intraindividual and interindividual variation of LPV-plasma levels, CD-4 increase, HI-virus suppression and liver tests in patients with and without liver disease is comparable. In this clinical setting no differences in LPV-plasma levels between patients with and without chronic liver disease could be demonstrated. LPV-therapy in patients with chronic liver disease is therefore safe. In patients with impaired liver function TDM is a helpful tool for dose adjustment.

Topics: Adult; Aged; Anti-HIV Agents; CD4 Lymphocyte Count; Chromatography, High Pressure Liquid; Chronic Disease; Drug Monitoring; Female; Humans; Liver Diseases; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies

Chronic atrial fibrillation (AF) is characterized by a marked decrease in the atrial effective refractory period (ERP) and in the ERP adaptation to rate as well as a decrease in the atrial conduction velocity. Little information is available about the ionic mechanisms underlying AF in humans.. We studied the effect of IKr blocker nifekalant on the rate-dependent changes in atrial action potential duration in 11 patients after successful internal cardioversion of chronic AF of >2 months duration and in 7 patients without AF. In AF patients, right atrial (RA) monophasic action potential (MAP) was recorded at pacing cycle lengths (CLs) of 800-250 ms before and after administration of nifekalant. In control patients, RAMAP was recorded at CLs of 600 and 350 ms before and after administration of nifekalant.. Nifekalant significantly increased RAMAPD at 90% repolarization (RAMAPD90) at CLs of 800-300 ms in the AF patients. The increase in RAMAPD90 by nifekalant became significantly smaller at shorter CLs (42.5 +/- 12.4 ms at a CL of 600 ms vs 32.8 +/- 14.5 ms at a CL of 350 ms, P < 0.05). Effect of nifekalant on RAPMAPD was attenuated at CL of 600 ms in AF patients in comparison to control patients (increase in RAMAPD in control; 73.0 +/- 36.6 ms vs increase in RAMAPD in AF; 42.5 +/- 12.4 ms, P < 0.05); however, it was similar at a CL of 350 ms between control and AF patients.. Electrophysiological effects of nifekalant are significantly attenuated in the chronically remodeled human atrium at slower heart rates, but the beneficial effect of RAMAPD prolongation by IKr blocker was well-preserved even at shorter CLs after chronic AF.

Topics: Action Potentials; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Chronic Disease; Electric Countershock; Female; Heart Atria; Heart Rate; Humans; Male; Middle Aged; Pyrimidinones; Refractory Period, Electrophysiological

To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development.. Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy.. The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >/= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level.. The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity.. Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.

Topics: Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Chronic Disease; Drug Therapy, Combination; Female; Hepatitis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Liver; Lopinavir; Male; Nelfinavir; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Saquinavir; Treatment Outcome

Topics: Acute Disease; Adolescent; Adult; Aged; Analgesics; Chronic Disease; Drug Evaluation; Humans; Joint Diseases; Middle Aged; Pyrimidinones