Biomedical subjects
Publications and source records attributed to T A Kelly.
Modification of the non-nucleoside inhibitor of HIV-1 reverse transcriptase nevirapine (Viramune) by incorporation of a 2-indolyl substituent confers activity against several mutant forms of the enzyme.
We reviewed the timing and mechanism of death in 1,184 consecutive patients with acute myocardial infarction (AMI) treated with primary angioplasty from 1984 to 1995. Of 98 deaths, 48 (49%) occurred early on day 0 or 1. The mechanisms of death were pump failure in 60 patients (61%), reinfarction in 7 patients (7.1%), left ventricular rupture in 5 patients (5.1%), arrhythmia in 3 patients (3.1%), other cardiac causes in 5 patients (5.1%), stroke in 6 patients (6.1%), anoxic encephalopathy in 7 patients (7.1%), and procedure-related deaths in 5 patients (5.1%). The strongest predictors of mortality were cardiogenic shock and unsuccessful reperfusion. Our data indicate that mortality after primary angioplasty, like thrombolytic therapy, is highest in the early hours and is usually due to pump failure. In contrast to thrombolytic therapy, the incidence of death from myocardial rupture and bleeding complications is low. Future treatment strategies will need to focus on the large number of patients with early death due to pump failure, especially patients with cardiogenic shock.
Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothizines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.
A series of prolineboronic acid (boroPro) containing dipeptides were synthesized and assayed for their ability to inhibit the serine protease dipeptidyl peptidase IV (DPPIV). Inhibitory activity, which requires the (R)-stereoisomer of boroPro in the P1 position, appears to tolerate a variety of L-amino acids in the P2 position. Substitution at the P2 position which is not tolerated include the D-amino acids, alpha,alpha-disubstituted amino acids, and glycine. Specificity against DPPII and proline specific endopeptidase is reported. A correlation between the ability to inhibit DPPIV in cell culture and in the human mixed lymphocyte reaction is demonstrated. A synthesis of prolineboronic acid is reported as well as conditions for generating the fully unprotected boronic acid dipeptides in either their cyclic or acyclic forms.
OBJECTIVES: The purpose of this study was to evaluate the importance of late infarct-related artery patency for recovery of left ventricular function and late survival after primary angio-plasty for acute myocardial infarction. BACKGROUND: Infarct-related artery patency is thought to improve late survival by its effect on preservation of left ventricular function. Patency may also enhance late survival by preventing left ventricular dilation and reducing arrhythmias, independent of myocardial salvage. However, most studies have not shown patency to be an independent predictor of survival when late left ventricular function is taken into account. METHODS: We followed up 576 hospital survivors of acute myocardial infarction treated with primary angioplasty for 5.3 years. Ejection fraction and infarct-related artery patency were determined at follow-up catheterization at 6 months. Predictors of late cardiac survival were determined using Cox regression models. RESULTS: Patients with patent arteries had more improvement and a better late ejection fraction than patients with occluded arteries (56.3% vs. 47.9%, p = 0.001). In patients with acute ejection fraction < 45%, late survival was better in those with patent versus occluded arteries (89% vs. 44%, p = 0.003), but patency was not a significant predictor after improvement in ejection fraction was taken into account. In patients with a large anterior infarction, patency was a significant independent predictor of late survival. CONCLUSIONS: Infarct-related artery patency is important for recovery of left ventricular function, and in patients with acute ejection fraction < 45%, patency is important for late survival. Our data are consistent with the hypothesis that the survival benefit is due primarily to the effect of patency on recovery of left ventricular function. In patients with a large anterior infarction, patency appears to provide an additional late survival benefit independent of myocardial salvage. These observations support the need for additional clinical trials of late reperfusion in patients with a large anterior infarction.
The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wild-type and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.
Molecular modeling analysis of the recently published X-ray crystal structure of nevirapine bound to wild type human immunodeficiency virus type 1 reverse transcriptase (WT-RT) indicated the presence of a lipophilic cavity proximal to the 4-position of the inhibitor. A series of 4-substituted derivatives of nevirapine were thus synthesized to assess structure-activity relationships (SARs) and to see if increased binding to this region might translate into greater activity against mutant RTs. The results show that compounds with an appropriately spaced aryl ring appended to the 4-position of the dipyridodiazepinone ring system show good activity against WT-RT. Furthermore certain derivatives appear to inhibit the Y181C mutant RT. Attempts to combine these results with the recent discovery that 2-substituents enhance activity against the Y181C mutant led to a few compounds with moderate activity against both enzymes. The SAR of these two positions, however, could not be combined in a simple fashion.
The benefit of thrombolytic therapy given late after the onset of acute myocardial infarction (AMI) has been controversial because of low reperfusion rates and limited myocardial salvage. Persistent chest pain has been used as a criteria for late intervention, but there is little documentation to validate this practice. Clinical outcomes and myocardial salvage were evaluated in 74 patients with AMI and persistent chest pain who underwent late reperfusion (> 6 hours) with direct coronary angioplasty, and these were compared with outcomes in 460 patients with early reperfusion (< or = 6 hours). Patients with late reperfusion had a high infarct artery patency rate (96%), a low hospital mortality rate (5.4%), and a low incidence of reinfarction (1.4%) and recurrent ischemia that were similar to patients with early reperfusion. Patients with late reperfusion had surprisingly good recovery of left ventricular function with improvement in ejection fraction from 50% to 60% at follow-up angiography. Patients with late reperfusion had a greater incidence of collateral flow (45% vs 22%, p < 0.001) and a lower value of peak creatine kinase (1,357 vs 2,057 U/liter, p < 0.001) than patients with early reperfusion. This study emphasizes the importance of persistent chest pain as a marker of continued myocardial viability in patients who present late after AMI. These data suggest that the probable mechanism of continued viability is preserved flow to the infarct zone. Patients with AMI and persistent chest pain may benefit from reperfusion therapy beyond 6 to 12 hours.
The importance of a patent infarct-related artery (IRA) for hospital and late survival was examined in 383 patients with acute myocardial infarction treated with direct coronary angioplasty. At hospital discharge, 317 of 348 patients (91%) had a patent IRA and mean follow-up left ventricular (LV) ejection fraction (EF) was 58%. Cardiac survival after hospital discharge at 1, 3 and 6 years was 99, 95 and 90%. Patency of the IRA was the most important determinant of hospital mortality: patent versus occluded IRA, 5 vs 39% mortality, p less than 0.001. Follow-up LVEF was the most important determinant of late cardiac mortality: follow-up LVEF greater than or equal to 45 versus less than 45%, 2 versus 24% mortality, p less than 0.001. Patency of the IRA was not a significant predictor of late cardiac mortality in the group as a whole: patent versus occluded IRA, 4.7 versus 6.5% mortality, p = 0.67. In the subgroup of patients with depressed initial LVEF less than 45%, patency was a significant predictor of late cardiac mortality: patent versus occluded IRA, 9.2 versus 40% mortality, p = 0.03. Patients with a patent IRA had better recovery of LV function than patients with an occluded IRA (follow-up LVEF 58.5 versus 47.6%, p less than 0.001). When late cardiac mortality was adjusted for differences in follow-up LVEF, patency was no longer a significant predictor of late mortality. Our results indicate patency of the IRA is the most important determinant of hospital survival, and LV function (measured after recovery) is the most important determinant of late cardiac survival.(ABSTRACT TRUNCATED AT 250 WORDS)
This study investigated (a) the nature and extent of perceived changes in patients' values (reported retrospectively), (b) the relationship between patients' assimilation of their therapists' values and outcome, and (c) the relationship between the similarity of patient-therapist values (posttherapy) and outcome. A great deal of perceived values change was reported by the patients, but (contrary to expectations) not primarily in values concerning interpersonal morality. Values assimilation demonstrated a fairly substantial positive correlation with therapist's outcome assessment, but not with other measures of outcome, suggesting that the phenomenon may be related more to the therapist's rating bias than to genuine improvement. Patient-therapist dyads whose values were moderately similar showed the most improvement, indicating that an intermediate range of values similarity may function as a predictor of positive outcome. Secondary findings (including the seemingly unique role of religious values) and suggestions for future research directions are discussed.
Coronary angioplasty without prior thrombolytic therapy was performed in 383 patients with acute myocardial infarction (AMI). Patients were divided into 2 groups depending on whether they were candidates or non-candidates for thrombolytic therapy. Patients were not considered thrombolytic candidates if they: (1) presented in cardiogenic shock, (2) were greater than or equal to 75 years of age, (3) had had coronary artery bypass surgery or, (4) had a reperfusion time of greater than 6 hours. Thrombolytic and nonthrombolytic candidates had similar rates of reperfusion (92 vs 88%), nonfatal reinfarction (6.0 vs 5.9%) and recurrent myocardial ischemia (1.8 vs 0%). Thrombolytic candidates had a lower mortality rate (3.9 vs 24%, p less than 0.0001) and a lower incidence of bleeding (4.6 vs 10.9%, p less than 0.05). Improvement in left ventricular ejection fraction at follow-up angiography was 4.4% in thrombolytic and 10.5% in nonthrombolytic candidates (p less than 0.002). Ejection fraction improved most in patients with anterior wall AMI (7.7% in thrombolytic candidates, 15.1% in nonthrombolytic candidates) and in patients with reperfusion times greater than 6 hours (14.2%). These outcomes suggest that direct coronary angioplasty is a viable alternative method of reperfusion in patients with AMI who are candidates for thrombolytic therapy. Nonthrombolytic candidates are a high-risk group of patients. Direct coronary angioplasty may be beneficial in certain subgroups, especially for patients in cardiogenic shock and for patients presenting greater than 6 hours after the onset of chest pain with evidence of ongoing ischemia.
A new fluorescent reagent based on aluminum phthalocyanine has been developed for general application to immunoassay. This highly sensitive fluorophore, Ultralite 680, may be covalently attached to a variety of biological entities for use as a tracer. We report the use of an Ultralite 680-streptavidin-digoxin conjugate as a tracer in a direct, competitive, heterogeneous, fluorescent immunoassay of digoxin. The assay is performed manually with 50 microL of serum and no sample pre-treatment. Primary anti-digoxin antibody is incubated with a serum sample containing digoxin and Ultralite 680-streptavidin-digoxin. Bound and free tracer are separated, and the bound fluorescence is released and quantified with a commercially available spectrofluorometer. Assay precision was good (CV = 7.05% at a digoxin concentration of 2.00 micrograms/L) and results by our method correlated well with those by a conventional RIA (r = 0.9650, n = 24).
A 2-part prospective study was performed to evaluate the clinical outcome of patients with hemodynamically confirmed asymptomatic valvular aortic stenosis (AS). During phase 1, linear regression analysis showed continuous wave Doppler to be highly accurate in predicting catheterization measured peak systolic aortic valve pressure gradients in 101 consecutive patients aged 36 to 83 years (mean 65 +/- 8) with symptomatic AS. During phase 2, 90 additional patients (51 asymptomatic and 39 symptomatic) with Doppler-derived peak systolic aortic valve gradients greater than or equal to 50 mm Hg (range 50 to 132 [mean 68 +/- 19]) were followed for 1 to 45 months. Both groups of patients in phase 2 had similar Doppler gradients and clinical and auscultatory evidence of moderate to severe AS at baseline. Asymptomatic patients were younger (p = 0.01), had higher ejection fractions (p = 0.001) and were less likely to have an electrocardiographic strain pattern (p = 0.01) and left atrial enlargement (p = 0.02). End-diastolic wall thickness, left ventricular cross-sectional myocardial area and estimated left ventricular mass were 18% (p = 0.0001), 20% (p = 0.0008), and 29% (p = 0.002) greater in symptomatic patients. During 17 +/- 9 months of follow-up, 21 asymptomatic patients (41%) became symptomatic. Dyspnea was the most common initial complaint, occurring 2.5 and 4.8 times more often than angina and syncope, respectively. Compared with the 39 symptomatic patients, the 51 asymptomatic patients had a lower cumulative life table incidence of death from any cause (p = 0.002), and from cardiac causes (p = 0.0001) including sudden death (p = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS)
The lack of secondary infections or the delay in their appearance in immunodeficient individuals (specifically AIDS patients) previously immunized prior to their immune deficit points to an as yet overlooked mechanism in the immune response. It is proposed that on second exposure to the antigen (Ag) there is a unique Ag presentation that alters the Ag in such a way as to induced a state of tolerance.
The nervous and immune systems are shown to be interrelated. Steroids inhibit both regeneration and the immune response. Crushing injuries enhance regeneration. A synthesis of these apparently unrelated phenomena is formulated into an immune hypothesis of regeneration. Steroids, in suppressing the immune response, decrease lymphokine production and the subsequent stimulation of nerve cell regeneration. Crushing injuries to nerve fibers cause nerve protein to become antigenic, thereby eliciting the production of "non-toxic" antibodies, which paradoxically protect the nerve fibers from immune attack and cause an augmented lymphokine production and subsequent nerve cell regeneration.
I have described a patient in whom cardiac tamponade occurred as the initial clinical manifestation of SLE. Although pericarditis is a common clinical entity in SLE, cardiac tamponade with this disease is rare. If suspected, the diagnosis can be made by the proper selection of tests of serum and pericardial fluid, which should include the search for pericardial LE cells. This report emphasizes the importance of screening for connective tissue disease in patients with pericarditis.
The case reported herein illustrates an unusual form of nonobstructive hypertrophic cardiomyopathy which was associated with Wolff-Parkinson-White syndrome, myocardial ischemia and necrosis despite normal coronary arteries. The patient is unique since the hypertrophied myocardial segment was localized exclusively to the posterolateral free wall. Quantitative thallium-201 scintigraphy demonstrated reversible ischemia that corresponded precisely with this region of posterolateral hypertrophy. While the exact mechanism for ischemia in patients with hypertrophic cardiomyopathy and normal coronary arteries remains controversial, a functional rather than anatomic disturbance of blood flow seems likely.
Fifty-seven episodes of atrial flutter in 46 consecutive medically treated patients (aged 60 +/- 17 years) were treated by rapid atrial pacing. Thirty-three patients (72%) had structural heart disease. Most pacing trials were conducted in patients receiving digoxin (88%) and antiarrhythmic drugs (77%). In 51 of 57 trials (89%), patients were successfully converted to normal sinus rhythm. Multivariate analysis revealed that patients who had congestive heart failure and who were older were more likely to be refractory to pacing. Left atrial size did not influence outcome. Confirmation of local atrial capture with a bipolar atrial electrogram and use of multiple atrial pacing sites enhanced the success rate. Eight patients (17%) demonstrated sinus node suppression after atrial pacing; sinus node disease was previously unsuspected in 4 of these patients. These bradyarrhythmias were easily managed because a pacing catheter was already in place. The only significant complication was femoral vein thrombosis in 1 patient. It is concluded that atrial pacing is an effective, safe and convenient method for the elective conversion of atrial flutter in the general population of medically treated patients. This technique is an attractive alternative to transthoracic cardioversion, and may be preferable in many patients.