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Biomedical subjects

T K Jones

Publications and source records attributed to T K Jones.

At least 37 records · Page 2Linked to original sources
PubMed1999

The hemodynamic effects of propofol in children with congenital heart disease.

UNLABELLED: We studied the hemodynamic effects of propofol during elective cardiac catheterization in 30 children with congenital heart disease. Sixteen patients were without cardiac shunt (Group I), six had left-to-right cardiac shunt (Group II), and eight had right-to-left cardiac shunt (Group III). The mean (+/-SD) ages were 3.8+/-3.1 yr (Group I), 3.2+/-3.7 yr (Group II), and 1.0+/-0.6 yr (Group III). After sedation and cardiac catheter insertion, hemodynamic data and oxygen consumption were measured before and after the administration of propofol (2-mg/kg bolus, 50- to 200-microg x kg(-1) x min(-1) infusion), and values were compared by using a paired t-test (significance: P < 0.05). After the propofol administration, systemic mean arterial pressure and systemic vascular resistance decreased significantly and systemic blood flow increased significantly in all patient groups; heart rate, pulmonary mean arterial pressure, and pulmonary vascular resistance were unchanged. Pulmonary to systemic resistance ratio increased (Group I, P = 0.005; Group II, P = 0.03; Group III, P = 0.10). In patients with cardiac shunt, propofol resulted in decreased left-to-right flow and increased right-to-left flow; the pulmonary to systemic flow ratio decreased significantly (Group II, P = 0.005; Group III, P = 0.01). Clinically relevant decreases in Pao2 (P = 0.008) and Sao2 (P = 0.01) occurred in Group III patients. We conclude that propofol can result in clinically important changes in cardiac shunt direction and flow. IMPLICATIONS: The principal hemodynamic effect of propofol in children with congenital heart defects is a decrease in systemic vascular resistance. In children with cardiac shunt, this results in a decrease in the ratio of pulmonary to systemic blood flow, and it can lead to arterial desaturation in patients with cyanotic heart disease.

Anesthesia, General↗
PubMed1998

5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators.

A series of nonsteroidal human progesterone receptor (hPR) agonists, 5-alkyl 1,2-dihydrochromeno[3,4-f]quinolines, was synthesized and evaluated in cotransfection and competitive receptor binding assays. The 5-alkyl substitution was shown to be responsible for the agonist activity and substitution at C9 dramatically enhanced the potency. A number of analogues in this series showed activities similar to or better than progesterone in the cotransfection and binding assays and analogue 15 exhibited similar in vivo activity as medroxyprogesterone acetate (MPA) in murine uterine wet weight/mammary gland morphology assays.

Animals↗
PubMed1998

5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists.

A novel series of nonsteroidal progestins, 5-benzylidene-1, 2-dihydrochromeno[3,4-f]quinolines (2), was discovered, and a preliminary structure-activity relationship study around the 5-benzylidene ring generated several potent human progesterone receptor agonists (compounds 8, 16). These new progestins showed biological activities (EC50 = 5.7 and 7.6 nM) similar to progesterone (EC50 = 2.9 nM) in the cotransfection assay with high efficacy (132% and 166%) and binding affinity (Ki = 0.66 and 0.83 nM) similar to medroxyprogesterone acetate (MPA) (Ki = 0.34 nM). A representative analogue, 8, demonstrated similar oral potency to MPA in the uterine wet weight/mammary gland morphology assay in ovariectomized rats.

Animals↗
PubMed1998

Nonsteroidal progesterone receptor antagonists based on a conformationally-restricted subseries of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines.

A series of nonsteroidal human progesterone receptor (hPR) antagonists based on conformationally-restricted analogues of a 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline pharmacophore were synthesized and evaluated for their ability to bind to the human progesterone receptor and inhibit progesterone-stimulated reporter gene expression in mammalian cells.

Humans↗
PubMed1998

Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore.

A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesized and tested for functional activity on the human progesterone receptor isoform B (hPR-B) in mammalian (CV-1) cells. The lead compound LG001447 (1,2-dihydro-2,2, 4-trimethyl-6-phenylquinoline) was discovered via directed high throughput screening of a defined chemical library utilizing an hPR-B cotransfection assay. Electron-withdrawing substituents at the meta position of the C(6) aryl group afforded substantial improvements in hPR modulatory activity. Several analogues were able to potently block the effects of progesterone in vitro. Two compounds, 10 (LG120753) and 11 (LG120830) with potencies comparable or equal to the steroidal hPR antagonist onapristone (ZK98,299), were demonstrated to act as antiprogestins in vivo after oral administration to rodents. This is the first disclosure of orally active nonsteroidal antiprogestins.

Administration, Oral↗
PubMed1998

Preparation, resolution, and biological evaluation of 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinolines: potent, orally active, nonsteroidal progesterone receptor agonists.

Two potent nonsteroidal progestins from the 5-aryl-1, 2-dihydro-5H-chromeno[3,4-f]quinoline class (LG120746 and LG120747) were selected for scale-up, resolution, and biological evaluation of the purified enantiomers. For each quinoline, the levorotatory enantiomer was determined to be the more potent agonist of the human progesterone receptor isoform B (hPR-B) (EC50 < 3 nM), but the dextrorotatory enantiomers retained significant PR modulatory activity (EC50 < 200 nM). In two in vivo rodent models of progestational activity, a pregnancy maintenance assay and a uterine wet weight assay, the two eutomers displayed potent progesterone-like effects. In a third model for progestational activity, the mammary end bud assay, these compounds were significantly less active. These studies demonstrate that certain members of this class of selective progesterone receptor modulators display encouraging and potentially useful tissue-selective progestational effects.

Administration, Oral↗
PubMed1998

New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone.

A series of 2(1H)-pyrrolidino[3,2-g]quinolinones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinolinone, displayed moderate interaction with hAR, but more substituted analogues, particularly 6,7-disubstituted compounds, were potent hAR agonists in vitro.

Androgen Antagonists↗
PubMed1998

Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines.

A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure-activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.

Androgen Antagonists↗
PubMed1998

5-Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.

The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.

Animals↗
PubMed1998

5-Aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines as potent, orally active, nonsteroidal progesterone receptor agonists: the effect of D-ring substituents.

Several 5-(4-chlorophenyl)-1,2-dihydro-5H-chromeno[3,4-f]quinolines were prepared to determine the effects of substitution at C(8) and C(9) on the progestational activity of this pharmacophore. In combination with a halogen (F or Cl) at C(9), replacement of the C(5) aryl group with variously substituted aryl groups resulted in optimization of the progestational activity, affording compounds with in vitro activity greater than that of progesterone as measured by a cotransfection assay using human progesterone receptor subtype-B (hPR-B). Binding affinities (Ki) to hPR-A were subnanomolar in many cases. These in vitro effects were verified in vivo using a rodent model. Compound 10 (LG120794, 9-chloro-5-(4-chlorophenyl)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno++ +[3,4-f] quinoline) was more potent than medroxyprogesterone acetate at counterpoising the effects of estradiol benzoate in the uterine wet weight assay using immature rats.

Animals↗
PubMed1998

Comparison of Ross procedures and aortic valve allografts in children.

BACKGROUND: The Ross procedure is useful, but at times an allograft valve is the only alternative to a mechanical aortic prosthesis. Since 1994 the Ross procedure or aortic allograft replacement has been used exclusively for aortic valve replacement at our institution. METHODS: Demographic, clinical, and echocardiographic data of 23 consecutive Ross and 8 allograft patients were compared. RESULTS: Groups were similar in age and weight. The Ross group had fewer prior operations. There were no deaths or major complications in either group. The Ross group had no late complications of the autograft but 1 reoperation for pulmonary allograft stenosis. In the allograft group there was one reoperation for allograft insufficiency. Echocardiography was performed 2 to 11 days (mean, 4.3 days) after operation and 1 to 28 months (mean, 10.2 months) later. In the Ross group left ventricular wall thickness (mm) decreased from 11.0 +/- 2.3 to 7.8+/-1.7 (p < 0.0001), and left ventricular outflow tract maximal systolic velocity (m/sec) decreased from 1.9 +/-0.6 to 1.4+/-0.4 (p = 0.0001). In the allograft group left ventricular wall thickness (mm) decreased from 10.5 +/-2.6 to 9.0+/-2.6 (not significant), and left ventricular outflow tract maximal systolic velocity (m/sec) increased from 1.5+/-0.9 to 1.9+/-0.7 (not significant). CONCLUSIONS: The Ross procedure results in significant improvement in left ventricular wall thickness and outflow tract velocity not seen in allograft aortic valve replacements. The Ross procedure remains the preferred operation for children requiring aortic valve replacement.

Adolescent↗
PubMed1998

Profound neonatal congestive heart failure caused by maternal consumption of blue cohosh herbal medication.

A newborn infant whose mother ingested an herbal medication, blue cohosh, to promote uterine contractions presented with acute myocardial infarction associated with profound congestive heart failure and shock. The infant remained critically ill for several weeks, although he eventually recovered. Other causes of myocardial infarction were carefully excluded. Blue cohosh, Caulophyllum thalictroides, contains vasoactive glycosides and an alkaloid known to produce toxic effects on the myocardium of laboratory animals. We believe this represents the first described case of deleterious human fetal effects from maternal consumption of blue cohosh.

Female↗
PubMed1997

Comparison of human tissues and mechanical prostheses for aortic valve replacement in children.

BACKGROUND: Aortic valve replacement in children is problematic because of complications of mechanical valves and uncertain outcomes associated with human valves. The results of pediatric aortic valve replacements over 5 years were reviewed. METHODS AND RESULTS: Mechanical valves were used exclusively during the first part of this series (n = 26). Thereafter, 25 consecutive aortic valve replacements were performed with autografts (n = 19) or allografts (n = 6). Allografts were used for Marfan's syndrome patients or those with unusable pulmonary valves. Among autograft/allograft recipients, 16 patients underwent 27 prior operations. In the mechanical group, 18 patients underwent 19 previous operations. Three patients in each group underwent a previous mechanical aortic valve replacement. Operative complications included two mild strokes and one pacemaker in the autograft/allograft group and three deaths and two pacemakers in the mechanical group. One autograft recipient required reoperation for pulmonary allograft stenosis. In the mechanical group, late complications included six cases of nonstructural degeneration and two cases of endocarditis, with three reoperations. Reoperation-free survival was 96% at 2 years in the autograft/allograft group and 80% at 2 years and 75% at 3 years in the mechanical group. Event-free survival was 96% at 2 years in the autograft/allograft group compared with 67% at 2 years and 49% at 3 years in the mechanical group (P < .05). CONCLUSIONS: The frequency of reoperations for mechanical aortic valve replacement has been surprisingly high. Aortic valve replacement in children with only autografts or allografts achieves good early results.

Adolescent↗
PubMed1996

Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists based on cyclocymopol monomethyl ether.

A novel class of nonsteroidal progesterone receptor antagonists has been synthesized and was shown to exhibit moderate binding affinity for hPR-A, the ability to inhibit the transcriptional activity of human progesterone receptor (hPR) in cell-based assays, and anti-progestational activity in a murine model. Cyclocymopol monomethyl ether, a component of the marine alga Cymopolia barbata was weakly active in random screening against PR. Investigations into the SAR surrounding the core of this natural product lead structure resulted in improved in vitro activity. In contrast to the cross-reactivity profiles observed with known steroidal antiprogestins, compounds of the general structural class described display a high degree of selectivity for the progesterone receptor and no functional activity on the glucocorticoid receptor.

Animals↗
PubMed1996

Discovery of novel intracellular receptor modulating drugs.

Utilizing the co-transfection assay as a guide to determining structure activity relationships, we have been pursuing the discovery of non-steroidal hPR modulators. Small molecule, non-steroidal lead structures have been identified. Optimization of these structures has yielded more potent hPR modulators. Improved cross-reactivity profiles with other intracellular receptors are a feature of these compounds owing to their non-steroidal nature.

Animals↗
PubMed1996

Acute results of balloon angioplasty of native coarctation versus recurrent aortic obstruction are equivalent. Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) Registry Investigators.

OBJECTIVES: This study sought to compare the immediate results and risk factors for suboptimal outcomes of percutaneous balloon angioplasty for native versus recurrent aortic obstruction. BACKGROUND: Some cardiology centers have been reluctant to adopt balloon angioplasty for treatment of native aortic coarctation, while advocating balloon angioplasty over an operation for treatment of postsurgical or recurrent aortic obstruction. METHODS: Acute results were analyzed from 970 procedures (422 native and 548 recurrent lesions) performed between 1982 and 1995 in 907 patients from 25 centers. An acute suboptimal outcome was defined as one or more of the following: residual systolic pressure gradient > or = 20 mm Hg, residual proximal to distal systolic pressure ration > or = 1.33 or a major complication (death, aortic transmural tear, stroke). RESULTS: Bal loon angioplasty significantly (p = 0.0001) increased lesion diameter fo r both native (mean [+/= SD] 128 +/= 94%) and recurrent aortic obstruction (97 +/= 87%), with a significantly greater increase in the native group (p = 0.0001). A reduction in systolic pressure gradients was significant in both groups (p = 0.0001), but slightly higher (p = 0.01) for native (-74 +/- 24%) versus recurrent obstruction (-70 +/- 31%). Death associated with angioplasty was reported in 0.7% of patients with native and in 0.7% of patients with recurrent lesions (p = 1.00). An acute suboptimal outcome was noted with angioplasty in 19% of native and in 25% of recurrent lesions (p = 0.04). Significant independent risk factors included higher preangioplasty systolic gradient (odds ratio [OR] 1.39/10-mm Hg increment; 95% confidence interval [CI] 1.28 to 1.50, p = 0.0001), earlier study date (OR 0.92/1-year increment, 95% CI 1.02 to 1.26, p = 0.02) and recurrent obstruction (OR 1.39 vs. native lesions, 95% CI 1.00 to 1.94, p = 0.05). CONCLUSIONS: Acute results and complications of balloon angioplasty of native coarctation appear to be equivalent or slightly superior to those of recurrent aortic obstructions.

Adolescent↗