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Biomedical subjects

J Edelson

Publications and source records attributed to J Edelson.

At least 19 recordsLinked to original sources
PubMed2001

Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease. METHODS: We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV(1)] 46.8% of predicted, FEV(1)/forced vital capacity [FVC] 54.6%, and postsalbutamol reversibility 5.4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV(1) before and after use of a bronchodilator. Analyses were by intention to treat. FINDINGS: Cilomilast 15 mg twice daily significantly improved FEV(1) compared with placebo (mean 130 mL vs -30 mL [95% CI 90-240] at week 6, p<0.0001). FVC and peak expiratory flow were also improved (p=0.001 and p<0.0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups. INTERPRETATION: Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Expanding the epidemiologic profile: risk factors for active tuberculosis in people immigrating to Ontario.

BACKGROUND: Many people immigrating to Canada come from countries with a high burden of tuberculosis. The aim of this study was to develop a detailed epidemiologic profile of foreign-born people with tuberculosis living in Ontario. METHODS: In this population-based case-control study, cases of tuberculosis diagnosed in 1994-1995 were identified from the database of the Ontario Reportable Disease Information Service and were considered eligible for analysis if a record of landing (receipt of permission to establish residence in Canada) from the period 1986-1995 was found in the Citizenship and Immigration Canada (CIC) database, if the person was at least 11 years of age at the time their visa was issued, and if the person had not been diagnosed with tuberculosis before becoming legally landed in Canada. Control subjects, who met the same criteria as the case subjects but who did not have tuberculosis in 1994-1995, were identified from a CIC database for landed immigrants. RESULTS: A total of 1341 cases of tuberculosis in foreign-born people were reported in Ontario in 1994-1995. A record of landing was found in CIC databases for 1099 of these people, 224 of whom were not legally landed at the time of diagnosis. In total, 602 cases met the inclusion criteria. The 2 strongest determinants of risk among those who had become landed within the preceding 10 years were referral for medical surveillance by immigration officials (odds ratio [OR] 3.8, 95% confidence interval [CI] 2.6-6.0) and world region of origin (Somalia [OR 67.7, 95% CI 31.3-154.9], Vietnam [OR 25.0, 95% CI 12.5-50.0], the Philippines [OR 11.9, 95% CI 6.0-23.3], other sub-Saharan African countries [OR 11.6, 95% CI 5.7-23.2], India [OR 9.7, 95% CI 4.9-18.9], China [OR 6.1, 95% CI 3.1-12.1], other Asian countries [OR 4.7, 95% CI 2.4-9.1], the Middle East [OR 4.1, 95% CI 2.0-8.3], Latin America [OR 1.9, 95% CI 0.9-3.8), and the former socialist countries of Europe [OR 1.8, 95% CI 0.8-3.8]; the reference category was countries with established market economies). Low socioeconomic status was an independent risk factor. INTERPRETATION: The risk of tuberculosis in groups of people migrating to Ontario is highly variable and is influenced by several factors. Successful population-based tuberculosis prevention strategies will need to accommodate this variability.

Adolescent↗
PubMed1995

Inhibition of fibroblast growth by epithelial cells in fetal rat lung.

The canalicular and saccular stages of rat lung development are marked by thinning of mesenchymal tissue. Because cell-cell interactions are important for normal fetal lung development, we investigated whether this regression of mesenchymal tissue is controlled by fibroblast-epithelial cell interactions. Using flow cytometry, thymidine uptake into DNA, and cell doubling time, we observed an increase in the proportion of lung fibroblasts in the G0/G1 phase of the cell cycle with advancing gestation. Conditioned medium of epithelial cells from the canalicular stage of lung development, but not from the pseudoglandular and saccular stages, inhibited fetal lung fibroblast proliferation. Fetal lung epithelial cell growth was not affected by the epithelial cell-conditioned medium. The response of fibroblasts to this epithelial cell-derived growth-inhibitory activity was organ specific but not gestation dependent. The inhibitory effect of epithelial cell-conditioned medium on fibroblast proliferation was overcome by the addition of > 2% fetal bovine serum. The inhibition was not mediated by prostaglandins because 50 microM ibuprofen, a prostaglandin synthase inhibitor, did not block the elaboration of the inhibitory activity by fetal lung epithelial cells. Partial characterization of the fibroblast growth-inhibitory activity in epithelial cell-conditioned medium showed that it was trypsin labile, heat and acid insensitive, and lipid extractable. Its molecular weight appears to be > 3.5 and < 12.5 kD. Transforming growth factor-beta 1 and surfactant proteins B and C did not mimic the inhibitory effect of epithelial cell-conditioned medium. These data suggest that fetal lung epithelial cells elaborate a hydrophobic polypeptide that inhibits fetal lung fibroblast proliferation in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1994

Ontogeny and regulation of platelet-derived growth factor gene expression in distal fetal rat lung epithelial cells.

Using flow cytometry, thymidine uptake into DNA, and expression of two growth-related genes, histone 3 and c-myc, we found an increase in the proportion of distal lung epithelial cells in the G0/G1 phase of the cell cycle with advancing gestation. Since our previous studies had demonstrated that platelet-derived growth factor (PDGF) is essential for the progression of these cells from the G0/G1 to the S phase of cell cycle, we investigated the gene and protein expression of PDGF-related genes (PDGF-A, PDGF-B, alpha-receptor, and beta-receptor) in distal fetal lung epithelial cells. The cells transcribed all the PDGF-related genes and translated the PDGF-A and PDGF-B mRNAs into protein, as demonstrated by immunocytochemistry and immunoprecipitation. To explore an autocrine role for PDGF in distal fetal lung epithelial cells, intervention studies using PDGF-A and -B chain-specific antisense oligodeoxynucleotides (ODN) were carried out. Antisense PDGF-B ODN, but not antisense PDGF-A ODN, significantly reduced the DNA synthesis of these cells. The inhibitory effect of antisense PDGF-B ODN on DNA synthesis was reversed by the addition of exogenous PDGF-BB, which supports an autocrine role in the DNA synthesis of these cells. We also examined the expression of PDGF genes in distal fetal lung epithelial cells during late gestation. PDGF-A chain and beta-receptor gene expressions declined with advancing gestation, whereas expression of message for PDGF-B chain and alpha-receptor increased. The increases in message for PDGF-B chain and alpha-receptor with advancing gestation were due to a greater rate of transcription, whereas the developmental decrease of PDGF-A chain and beta-receptor mRNAs was caused by a decrease in RNA stability. Taken together with the ODN data, these results suggest that the G0/G1 cell cycle arrest of distal lung epithelial cells during late fetal gestation is due to a decrease in PDGF beta-receptor expression by the cells.

Animals↗
PubMed1993

Expression of the epithelial Na+ channel in the developing rat lung.

The adult mature fetal, but not immature fetal, lung is capable of actively transporting Na+ from the alveolar space. The reason for the impaired Na+ transport in the immature lung is not known; however, the apical membrane Na+ channel is the rate-limiting step for epithelial Na+ transport. This study determined whether transcripts coding for the adult rat colonic epithelial Na+ channel (alpha rENaC) were present in the fetal and adult lung and whether they were developmentally regulated. Similarly sized alpha rENaC transcripts were identified in RNA isolated from fetal and adult whole rat lung, primary cultures of fetal and adult alveolar epithelium, and adult rat whole kidneys, suggesting that the lung alpha rENaC is a similar transcript to that found in the salt-deprived rat colonic epithelium. There were low mRNA levels in 17- to 18-day gestational age (GA) fetal lungs and epithelium (term GA = 22 days), but these levels increased markedly during the saccular stage of lung development (20 days GA) and remained high in adult lungs. The combined administration of thyroid-releasing hormone and dexamethasone to pregnant rats between 16 and 18 days GA induced the expression of lung alpha rENaC in their fetuses. We conclude that alpha rENaC is expressed in mature fetal and adult alveolar epithelium and that it is influenced by hormones known to alter maturation of the fetal lung.

Aging↗
PubMed1993

Extracellular phospholipase A2 expression and inflammation: the relationship with associated disease states.

Human non-pancreatic PLA2 has been the object of intense scrutiny for a relatively short period of time. Its role in physiology remains enigmatic. While PLA2 may serve to remodel or remove peroxidised or senescent phospholipids, the enormous magnitude of its upregulation during infectious or inflammatory episodes is consistent with a role in host defense. However, the nature of this role remains elusive. Attempts to relegate this enzyme to the genre of acute phase reactants have not been helpful in unravelling its role. Difficulty in obtaining adequate amounts of native snp-PLA2 prior to the availability of recombinant snp-PLA2 led to the widespread use of snake venom homologs, particularly in studies of the biology of PLA2. This review has underscored the pitfalls inherent in that approach given the major differences between some venom PLA2s as compared to snp-PLA2. In addition, it bears reiterating that the complex composition of venom allows for potentiation of PLA2 activity by other constituents present in venom. Whether human host defense networks employ this interactive strategy is largely unknown. Nonetheless, in spite of these reservations, some very compelling data have emerged in recent years implicating snp-PLA2 in the initiation or potentiation of local and systemic inflammatory processes. These include sepsis and associated acute lung injury as well as inflammatory arthritides, with rheumatoid arthritis as the prototype. The mechanisms of snp-PLA2 homeostasis are considerably better understood, and it has become apparent that snp-PLA2 is an integral part of a larger network of proinflammatory cytokines, growth factors and lipid mediators. The interrelationship between the functions of secretory and cytosolic PLA2s remains to be defined. A number of selective PLA2 inhibitors have been identified which will allow for discrimination between the actions of these classes of PLA2. The availability of synthetic inhibitors in conjunction with endogenous modulators of PLA2s will shift the biology of PLA2 from the realm of the inferential to that of the mechanistic.

Animals↗
PubMed1989

A comparison of cognitive-behavioral and hypnotic treatments of chronic pain.

Twenty-seven chronic pain patients were assigned to one of three treatment groups: hypnosis, cognitive-behavioral, and an attention control. Hypnosis and cognitive-behavioral treatments were identical with the exception of the hypnotic induction. Scores on the McGill Pain Questionnaire (MPQ) and the Activity Log (Fordyce, 1976) were collected at pretreatment, posttreatment, and follow-up intervals. Analyses of changes showed significant increases in activity and decreases in pain intensity for the cognitive-behavioral treatment. Changes for the hypnosis treatment were noted only on the MPQ. Changes for both groups were sustained on the 1-month follow-up. Results of ANCOVAs showed that the cognitive-behavioral treatment resulted in significantly lower pain rating scores than those in the control treatment, but no significant differences were observed between the behavior and hypnosis groups. Findings support the superiority of the cognitive-behavioral treatment on behavior measures and equivalence to hypnosis on subjective measures.

Adult↗
PubMed1986

Effect of the acetylator phenotype on amrinone pharmacokinetics.

Ten healthy male subjects were phenotyped with isoniazid for their acetylator status and then received intravenous amrinone at a dose of 75 mg during a period of 10 minutes. Blood samples were drawn at specified times during a 24-hour period after dosing. Plasma concentrations of amrinone were determined by a specific HPLC method. The plasma concentration data were fitted to a biexponential model by nonlinear regression. The mean apparent first-order elimination t1/2 for amrinone in the slow acetylators was 4.4 hours, whereas it was 2.0 hours in the fast acetylators (P less than 0.05). There was little difference in the volume of distribution at steady state. Clearance was lower in the slow acetylators, 16.6 L/hr, than in the fast acetylators, 37.2 L/hr (P less than 0.05). The AUC was higher for the slow acetylators, 4.96 micrograms X hr X ml-1, than for the fast acetylators, 2.20 micrograms X hr X ml-1 (P less than 0.01). Concentrations of amrinone and its N-acetyl metabolite in the urine from each volunteer were determined. The ratio of N-acetylamrinone to amrinone was calculated and, as expected, the fast acetylators had a higher ratio than did the slow acetylators (P less than 0.01).

Acetylation↗
PubMed1986

Pharmacokinetics of the bipyridines amrinone and milrinone.

The pharmacokinetics of milrinone were studied in sequential ascending doses in New York Heart Association Class III and IV patients receiving oral and intravenous medication. The parameters determined after parenteral administration were estimated by fitting the plasma concentration data to an open two-compartment body model. After oral medication, regression-independent parameters were determined. After either oral or parenteral administration of milrinone, plasma levels were dose dependent and the drug had an apparent first-order terminal elimination half-life of approximately 2 hr. The apparent volume of distribution was approximately 400 to 500 ml/kg, and total body clearance was approximately 130 ml/kg/hr. These values obtained in patients receiving milrinone were compared with those obtained for milrinone in volunteers, as well as those noted with the other inotropic bipyridine, amrinone. Milrinone's elimination from the blood stream patients was slower that that in normal healthy subjects and faster than amrinone's elimination in patients with congestive heart failure. Milrinone's pharmacokinetic parameters in these patients were unchanged after approximately 30 days of continuous oral medication.

Administration, Oral↗
PubMed1985

Determination of fezolamine and its desmethyl metabolite in human plasma and urine by high-performance liquid chromatography. Intravenous pharmacokinetics in the beagle hound.

Sensitive and selective high-performance liquid chromatographic methods for the quantitation of the experimental antidepressant fezolamine and its desmethyl metabolite in plasma and urine have been developed. Both assays are linear between 0 and 500 ng/ml in both plasma and urine and have calculated minimum quantifiable levels of less than 10 ng/ml. Statistical evaluation of analytical parameters under single-blind conditions demonstrated an overall precision within +/- 4% of nominal for both compounds in either biological medium. The overall accuracies of the assays were within +/- 5% of nominal values in urine and +/- 10% of nominal values in plasma. Following intravenous administration of fezolamine fumarate to beagle hounds, a biexponential decline in drug plasma levels was observed with the first phase having a half-life of about 11 min and the second phase about 2.6 h. Peak plasma levels of the metabolite were observed at 2 h. Recovery of the parent drug in urine was less than 5% of the administered dose and less than 1% for the desmethyl metabolite.

Animals↗
PubMed1984

Relative bioavailability and pharmacokinetics: a combination of pentazocine and acetaminophen.

The relative bioavailability and pharmacokinetics of a combination product containing pentazocine and acetaminophen were studied in 20 healthy human males. Each subject, in a single-dose three-way crossover design, received two different preparations containing 50 mg of pentazocine (as base) and 1300 mg of acetaminophen either as capsule-shaped tablets or as a solution. Plasma concentrations of pentazocine and acetaminophen were determined from 0.25 to 12 h following oral administration. The plasma data for both compounds in the tablet formulation were described by an open one-compartment body model with first-order absorption. The average (+/- SD) bioavailability of the tablet relative to that of the solution was 85.0 +/- 31.1 and 88.6 +/- 13.1% for pentazocine and acetaminophen, respectively. The apparent first-order regression-dependent elimination rate constants for pentazocine from the tablet and solution preparations were 0.19 +/- 0.08 and 0.20 +/- 0.06 h-1, respectively, while the rate constants for acetaminophen were 0.26 +/- 0.03 and 0.25 +/- 0.03 h-1 for the tablet and solution preparations, respectively. These rate constants correspond to terminal elimination half-lives of approximately 3.6 h for pentazocine and approximately 2.7 h for acetaminophen.

Acetaminophen↗
PubMed1984

Pharmacokinetics of iohexol, a new nonionic radiocontrast agent, in humans.

Sixteen healthy men received iohexol intravenously at a concentration of 346 mg of iodine/mL. Doses of 500, 750, 1000, and 1500 mg of iodine/kg of body weight were administered to four volunteers each. Neither clearance nor percent of dose excreted in the urine showed any significant correlation with size of the dose. The overall mean (+/- SD) renal and total body clearances were 120 +/- 18.6 and 131 +/- 18.6 mL/min, respectively. The overall mean apparent volume of distribution was 165 (+/- 30.7) mL/kg. Urine contained 92.3 +/- 4.4% of the dose. Most of the drug (89.9%) was excreted within the first 12 h. An open three-compartment body model gave the best fit to the experimental data. The mean apparent first-order terminal elimination (gamma-phase) half-life was 12.6 h.

Adolescent↗
PubMed1984

Oral and intravenous pharmacokinetics of milrinone in human volunteers.

Thirty-nine healthy men received milrinone either orally or intravenously in two separate double-blind, placebo-controlled studies. The mean bioavailability, based on the area under the plasma concentration versus time curves, was 0.92. The plasma data for those subjects in the intravenous study were described by an open two-compartment model with a mean (+/- SD) apparent first-order terminal elimination rate constant (beta) of 0.86 (+/- 0.23) h-1, which corresponds to a half-life of 0.8 h. In the intravenous study, the renal clearance and total body clearance were 21.1 and 25.9 L/h, respectively. The corresponding values in the oral study were 23.8 and 29.7 L/h. Between 79.9 and 84.5% of the total doses were recovered in the urine samples taken at 0-24 h.

Administration, Oral↗
PubMed1984

Correlation of the hemodynamic and pharmacokinetic profile of intravenous milrinone in the anesthetized dog.

The relationship between the hemodynamic effects of milrinone and its plasma concentration was studied in the anesthetized instrumented dog. Milrinone was administered intravenously either as a single bolus of 10, 30 or 100 micrograms/kg or infused at a rate of 10 micrograms/kg/min. The changes in drug plasma concentration and cardiovascular parameters were determined simultaneously during the course of drug action. The intravenous bolus injections of milrinone caused dose-dependent increases in its maximum plasma concentration that resulted in concomitant increases in both cardiac contractile force and heart rate with simultaneous decreases in systolic and diastolic blood pressure. The intravenous infusion of milrinone caused parallel increases in both drug plasma concentration and cardiac contractile force; following termination of the milrinone infusion, there was a gradual decline in both its plasma concentration and in its inotropic activity, with a similar time course for these two parameters. A positive correlation (r = 0.78; p less than 0.008) was obtained between milrinone plasma concentration and its inotropic effect.

Anesthesia↗
PubMed1983

Evaluation of a new bipyridine inotropic agent--milrinone--in patients with severe congestive heart failure.

Milrinone, a derivative of amrinone, has nearly 20 times the inotropic potency of the parent compound and does not cause fever or thrombocytopenia in normal volunteers or in animals sensitive to amrinone. In 20 patients with severe congestive heart failure, intravenous milrinone resulted in significant decreases in left ventricular end-diastolic pressure (from 27 +/- 2 to 18 +/- 2 mm Hg), pulmonary wedge pressure, right atrial pressure, and systemic vascular resistance, as well as a slight reduction in mean arterial pressure. Significant increases occurred in cardiac index (from 1.9 +/- 0.1 to 2.9 +/- 0.2 liters per minute per square meter) and the peak positive first derivative of left ventricular pressure, with a slight increase in heart rate. Hemodynamic improvement was sustained during a 24-hour continuous infusion. Nineteen of the 20 patients subsequently received oral milrinone (29 +/- 2 mg per day) for up to 11 months (mean, 6.0 +/- 0.8), with sustained improvement in symptoms of heart failure. In 10 patients receiving long-term oral milrinone (greater than or equal to 6 months) radionuclide ventriculography showed continued responsiveness, with a 27 per cent increase in left ventricular ejection fraction after 7.5 mg of the drug. Four patients died after a mean of 4.8 months of therapy, and three patients with severe underlying coronary-artery disease and angina pectoris required additional antianginal therapy. No patient had fever, thrombocytopenia, gastrointestinal intolerance, or aggravation of ventricular ectopy. We conclude that milrinone shows promise for the longterm treatment of congestive heart failure.

Administration, Oral↗