Biomedical subjects
Publications and source records attributed to G Koren.
By performing single pass experiments in the dog, we could identify by thin layer chromatography a digoxin metabolite produced by the kidney. In vitro studies verify that this new species is produced by the brush border membrane of the renal tubular cell.
Expression of the cardiac myosin isozymes is regulated during development, by hormonal stimuli and hemodynamic load. In this study, the levels of expression of the two isoforms (alpha and beta) of myosin heavy chain (MHC) during cardiac hypertrophy were investigated at the messenger RNA (mRNA) and protein levels. In normal control and sham-operated rats, the alpha-MHC mRNA predominated in the ventricular myocardium. In response to aortic coarctation, there was a rapid induction of the beta-MHC mRNA followed by the appearance of comparable levels of the beta-MHC protein in parallel to an increase in the left ventricular weight. Administration of thyroxine to coarctated animals caused a rapid deinduction of beta-MHC and induction of alpha-MHC, both at the mRNA and protein levels, despite progression of left ventricular hypertrophy. These results suggest that the MHC isozyme transition during hemodynamic overload is mainly regulated by pretranslational mechanisms, and that a complex interplay exists between hemodynamic and hormonal stimuli in MHC gene expression.
Tubular secretion appears to be a major route of the renal elimination of digoxin. Secretion of the drug by the tubules is modulated by renal blood flow, by a number of commonly coadministered drugs (e.g. quinidine, spironolactone, verapamil, amiodarone), and by age. The maximal transport capacity does not appear to be achieved with clinically relevant concentrations. The tubular transport of digoxin does not appear to be associated with the anionic or cationic transport systems, nor the Na+/K+-ATPase receptor. Further studies are needed to elucidate the exact mechanisms involved in the transtubular movement of the glycoside.
Despite continuous controversy associated with a variety of aspects of the pharmacology of the cardiac glycosides, it appears that these agents will continue to be widely used in the future. Current methods for the measurement of digoxin are unreliable and allow measurement of both cardioinactive metabolites of digoxin and endogenous digoxin-like substances. As a result, the therapeutic monitoring of digoxin concentrations should, for the most part, be limited to an assessment of patient compliance and confirmation of a clinical impression of drug toxicity.
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Fifty-one successive patients treated with intravenous streptokinase 1.7 +/- 0.8 (mean +/- SD) hours after onset of symptoms of acute myocardial infarction were evaluated during a three-month posthospital follow-up period. Coronary angiography was performed four to nine days after the initial hospital admission. Twenty-eight patients had a second late angiogram. Forty-one patients had successful reperfusion but only 25% of all patients were without significant clinical cardiovascular manifestations during this period. Postmyocardial infarction angina pectoris occurred in 21 patients, an abnormal stress test result was present in 28 patients, eight patients developed congestive heart failure, and five patients had reinfarction. An intervention with percutaneous transluminal coronary angioplasty or coronary artery bypass graft was performed in 15 (37%) of 41 reperfused patients. A significantly higher intervention rate was present in patients treated with streptokinase within one hour following the onset of symptoms. Early reocclusion (within three months of the infarct) was noted in patients with 60% or more residual stenosis in their infarct-related coronary artery. These patients also had a significantly greater incidence of angina pectoris. Our findings indicate that early thrombolytic therapy of acute myocardial infarction preserves myocardium, and since the infarct-related artery is patent, but narrowed, the jeopardized area is responsible for a high-risk syndrome with an increased likelihood of ischemic symptoms. An early aggressive approach may be indicated, especially for patients with greater than 60% residual stenosis in their infarct-related coronary artery.
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The importance of timing of intravenous streptokinase (SK) administration in patients with acute myocardial infarction (AMI) was evaluated. Intravenous SK, 750,000 U, was administered within 4 hours of the onset of ischemic chest pain to 72 consecutive patients having their first AMI. Six days later, cardiac catheterization was performed to calculate global ejection fraction (EF), and computer-derived infarct-related regional EF and dysfunction index were also determined; electrocardiograms were recorded, from which QRS scores could be calculated to estimate infarct size. Of 19 patients who had an anterior AMI, 12 (63%) who received intravenous SK within 2 hours after onset of pain sustained only minimal damage in terms of global EF, infarct-related EF, dysfunction index and QRS score. All 10 patients who received SK 2 to 4 hours after pain onset had large infarcts (p less than 0.001). Of the former group, 11 of 12 patients (91%) whose pain was relieved within 1.5 hours of intravenous SK administration (presumably due to successful reperfusion) had a good outcome, whereas all 7 whose pain lasted longer did poorly (p less than 0.001). Furthermore, among patients with anterior AMI, 11 of 14 (79%) whose pain was relieved within 3.5 hours of onset had small infarcts, compared with none of the 12 patients whose pain lasted longer (p less than 0.0001). In inferior AMI, the critical time between onset of pain and initiation of intravenous SK was 1.5 hours (p less than 0.05). The timing of initiation of thrombolytic therapy and the total pain duration are critical in determining outcome in AMI, and time intervals vary depending on infarct localization.
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We treated three unrelated patients with hemophilia A and congenital pulmonary valve stenosis. In two patients, the occurrence of the cardiac malformation was sporadic and in one familial. The coexistence of hemophilia A and pulmonary valve stenosis might suggest a genetic linkage for both disorders. Review of the literature supports the hypothesis that the inheritance of pulmonary valve stenosis is dominant and X-linked.
Fentanyl-oxygen (fentanyl-O2) anaesthesia was compared to fentanyl-nitrous oxide/oxygen (fentanyl-N2O/O2) anaesthesia in 14 children undergoing cardiac surgery. Children were randomly assigned to one of the two techniques studied, with seven patients in each group. The mean age (mean +/- SE) was 3.9 +/- 0.75 years (0.5-8.25 years) and mean weight 14.7 +/- 2 kg (3.5-29.5 kg). Patients were premedicated with IM atropine 0.02 mg . kg-1 and morphine 0.2 mg . kg-1 1 hour preoperatively. They received a fentanyl bolus of 30 micrograms . kg-1 with a concomitant continuous infusion of 0.3 micrograms . kg-1 . min-1. Pancuronium 0.1 mg . kg-1 was administered immediately following the fentanyl bolus. Fifty per cent nitrous oxide was given with oxygen in one group and 100 per cent oxygen was administered to the other group. Fentanyl plasma concentrations were similar in the two groups at the various stages of surgery. There were no significant differences between the two treatment groups in systolic and diastolic blood pressure or in heart rate in response to induction, intubation, and incision. There was a significantly greater increase in systolic blood pressure after sternotomy in the fentanyl-O2 group. In addition, in six of seven patients receiving fentanyl-O2 there were events of sudden increase in blood pressure during various stages of surgery before the bypass, necessitating an additional fentanyl bolus or the addition of droperidol in four cases. Similar phenomena were not documented in the fentanyl-N2O/O2 group. Our studies suggest that fentanyl-O2 anaesthesia in the schedule described, in children undergoing elective cardiac surgery for Tetralogy of Fallot, A-V canal, and transposition of the great arteries, is not sufficient to prevent elevation in systolic blood pressure despite fentanyl plasma concentrations in excess of 20 ng X ml-1. The addition of nitrous oxide prevents this phenomenon.
Acute myocardial infarction, particularly of the inferior wall, is frequently associated with bradycardia and hypotension. This study reports the occurrence of transient bradycardia hypotension (TBH) (Bezold-Jarisch reflex) following thrombolytic therapy with intravenous streptokinase. Of the 52 patients, 42 had successful reperfusion, and 12 of the latter developed reflex TBH. The Bezold-Jarisch reflex occurred in 10 of 24 patients with inferior wall acute myocardial infarction and in 2 of 28 patients with anterior wall infarction (p less than 0.05). The reflex was associated with significantly more non-Q wave infarctions (p less than 0.05) and also with reduction of left ventricular damage, as evidenced by a lower QRS score (4 +/- 3.8 vs 8.9 +/- 5.6, p less than 0.01) and a higher ejection fraction (61 +/- 13% vs 49 +/- 16%, p less than 0.05). Patients with inferior wall acute myocardial infarction were divided into those with TBH (10 patients) and those without TBH (14 patients). TBH was associated with a significantly higher infarct-related regional ejection fraction (60 +/- 19% vs 35 +/- 18%, p less than 0.05). The results of this study confirm previous findings that reperfusion of the inferoposterior myocardium is capable of stimulating reflex TBH. Furthermore, TBH is associated with patency of infarct-related coronary arteries and myocardial salvage.
Intravenous streptokinase (STK) was given in the field by a physician-staffed mobile intensive care ambulance to 13 patients. Patients waited 33 +/- 17 minutes to call the ambulance, arrival time was 5 +/- 3 minutes, and a further work-up time of 32 +/- 8 minutes elapsed. The average time from the onset of pain until administration of STK was 66.7 minutes. Patients were transferred to hospital without important side effects or complications. Eleven of 12 of the infarction-related arteries were patent on subsequent coronary angiography. Three patients had minor hematomas and two had microscopic hematuria. This pilot study shows that intravenous STK can be given with relative ease and safety at home by an experienced physician capable of treating any complications.
Between June 1, 1979, and May 31, 1984, at The Hospital for Sick Children in Toronto, Kawasaki disease was diagnosed in 163 patients (112 boys, 51 girls, P less than 0.001). Fifteen percent of the children had coronary artery aneurysms. Prior to diagnosis, 24% had been given low doses of aspirin, and 50% acetaminophen. Children with coronary aneurysms had significantly higher temperature during days 10 to 13 of the disease. The febrile phase of the disease was also significantly longer in these children. Coronary artery involvement occurred with equal frequency in boys and girls. There was no significantly greater incidence of coronary artery involvement in infants younger than 1 year of age than in older children. Duration of fever (greater than or equal to 14 days vs less than 14 days) was equally as predictive of the eventual occurrence of coronary aneurysms as the modified Asai score.
Primary invasive cutaneous mucormycosis in a non-immunocompromised patient is described. Cultures from the infected tissues yielded a zygomycete which was identified as Saksenaea vasiformis. The patient was successfully treated with debridement of the lesion and amphotericin B.