The effects of delta1-cortienic acid on skin blanching, pharmacokinetics and stability of loteprednol etabonate.

The effect of delta1-cortienic acid (delta1-CA) on human skin blanching activity of the soft corticosteroid, loteprednol etabonate (LE), has been studied. Ten volunteers had applied to their forearms a dose of LE ranging from 0.1 to 1 mM, or LE from 0.1 to 1 mM in combination with 2-times the concentration of delta1-CA (0.2 - 2mM). The results indicate that delta1-CA increased LE's effect on human vasoconstriction/skin blanching activity, both in the intensity and duration. This enhancing effect of delta1-CA was also observed in other blanching studies with other corticosteroids, such as hydrocortisone. The enhancement may occur through the displacement of LE bound to transcortin (also known as corticosteroid-binding globulin, or CBG) by delta1-CA as delta1-CA has a higher affinity for CBG than that for glucocorticoid receptor (GR), resulting in more free-LE to act on GR, and increased skin blanching. In rat studies, intravenous injection of delta1-CA (5-50 mg/kg) did not affect the pharmacokinetics of LE (5 mg/kg), indicating that delta1-CA is safe for combined use with LE. In stability studies, the presence of delta1-CA at the same concentrations as LE in aqueous suspension (0.1 and 0.2%) significantly increased the stability of LE. Thus, the combination of delta1-CA with LE serves an enhancing and stabilizing role while not impacting the pharmacokinetic properties of LE.

Nicotinic acid: an old drug with a promising future.

Nicotinic acid has been used for decades to treat dyslipidaemic states. In particular its ability to raise the plasma HDL cholesterol concentration has led to an increased interest in its pharmacological potential. The clinical use of nicotinic acid is somewhat limited due to several harmless but unpleasant side effects, most notably a cutaneous flushing phenomenon. With the recent discovery of a nicotinic acid receptor, it has become possible to better understand the mechanisms underlying the metabolic and vascular effects of nicotinic acid. Based on these new insights into the action of nicotinic acid, novel strategies are currently under development to maximize the pharmacological potential of this drug. The generation of both flush-reducing co-medications of nicotinic acid and novel drugs targeting the nicotinic acid receptor will provide future therapeutic options for the treatment of dyslipidaemic disorders.

Surgically treated intraoperative coronary embolism.

We report a case of intraoperative coronary embolism in a 52-year-old male patient undergoing mitral valve replacement. The patient had persistent atrial fibrillation and was treated with oral anticoagulants and, in spite of well controlled anticoagulation, he suffered a transient ischemic attack. No intracardiac thrombus was found by transthoracic echocardiography. Three weeks later open heart surgery was performed. During valve surgery no thrombus was found in the left atrium. When cardiopulmonary bypass was discontinued the heart function rapidly deteriorated and the heart swelled up, became bluish, with left atrial pressure rising to 40 mm Hg. It was noticed that the anterior surface of the left ventricle was not moving. Coronary embolism was considered. Multiple thrombi were found and removed from the left anterior coronary artery. After successful thrombectomy the patient came off the pump easily. Early and late postoperative course were uneventful. Intraoperative coronary embolism should be considered when cardiac function is deteriorating and there is an inability to wean the patient from the pump. Early and correct diagnosis is lifesaving.

[Experience with surgical treatment of prosthetic valve endocarditis]. / Múbillentyú-endocarditis sebészi kezelésével szerzett tapasztalataink.

Prosthetic valve endocarditis (PVE) is a rare but dangerous complication that may occur after the implantation. The authors retrospectively summarize their 11-year experience in treating PVE. 2357 prosthetic valve (PV) implantations were performed over 11 years at the Department of Cardiovascular Surgery, Semmelweis University, Budapest, PVE was found to be the indication for operation in 1.8% of the cases (43/2357). 43 surgical interventions were carried out on 38 patients (mean age: 52.5 yrs, male/female ratio: 25/13). Blood cultures were positive in 86% and negative in 14% of the cases. The infected PV-s were replaced emergently (14%), urgently (79%) or electively (7%). The explanted valves were aortic in 55% and mitral 45% of the cases, 63% were mechanical and 37% biological. PVE followed the primary PV implantation in less than a year in 39.5%. Infected environment during the primary PV implantation was found to be a predisposing factor for the late endocarditis episodes. The mean age of the infected and explanted aortic bioprosthetic valves was significantly higher than that of explanted mechanical valves (p < 0.05). No such difference could be found at the mitral valves. The explanted valves were replaced by mechanical (75.5%) or biological (22.5%) devices. Homograft was implanted once. Early postoperative mortality of the primary PV replacements was 10.5%) devices. Homograft was implanted once. Early postoperative mortality of the primary PV replacements was 10.5%. Endocarditis reoccurred in 20% of the cases. Means follow-up duration was 45.5 months. Two-, five- an 10-year survival were 75%, 64% and 51% respectively. In conclusion in the surgical treatment of PVE, bioprosthetic and mechanical valves are suitable alternatives as opposed to homografts and freestyle stentless valves.

[Biatrial pacing--new possibility in the non-pharmacologic treatment of drug-resistant paroxysmal atrial fibrillation]. / Biatrialis ingerlés--a gyógyszerrezisztens paroxizmális pitvarfibrilláció nonfarmakológiás kezelésének újabb lehetósége.

Biatrial pacing seems to be a possible non-pharmacological therapeutic choice in the prevention of drug-refractory, paroxysmal atrial fibrillation. Biatrial pacing using standard right atrial and coronary sinus left atrial pacing shows an antiarrhythmic effect, which mechanism is not well understood. Biatrial pacemaker was implanted in three patients suffering from drug refractory, symptomatic paroxysmal atrial fibrillation (lone and nonvalvular in 2 and in one case, respectively). Interatrial conduction disturbance (P > 120 ms) was found in three case. Bradycardia dependent arrhythmia development was not observed. Left atrial and right atrial premature beats dominated in 2 and in one case, respectively. P-wave duration was decreased by biatrial pacing in every patients. Atrial fibrillation has not been detected in two patients 1 day and 4 weeks after pacemaker implantation (follow up period: 9 and 5 months), however antiarrhythmic drugs has been withdrawn. In the number of left atrial premature beats a marked decrease was observed. Neither biatrial nor standard right atrial pacing nor combined medical and atrial pacing antiarrhythmic therapy were proven to be effective. In Hungary we were the first to implant and apply effectively biatrial pacemaker in the prevention of paroxysmal drug-refractory atrial fibrillation. However better identification the responding patients subgroup with atrial fibrillation is needed.

[Simultaneous carotid and coronary operations: experience and results of 11 years (1990-2000)]. / Szimultán végzett carotis-coronaria mútétek: 11 év tapasztalatai és eredményei (1990-2000).

Between 1990-2000 163 coronary + carotid procedures were performed. The mean age was 4 years higher than it was at patients underwent isolated CABG (63.4 y vs 59.8 y). Clinically proven obliterative artery diseases in other anatomical regions were also present in more than 60% of patients. The half of the procedures were performed under emergency and urgent circumstances. The cardiac status and the coronary morphology were found to be unstable in half of the patients. The "Euroscore" risk evaluation model was used for risk scoring. The mean score value was as high as 6.26. According to this the estimated surgical lethality could have been as high as 11.2%. The real surgical lethality value was far under this estimated level (7.36%). The 1, 5, 10 year survival rate were as high as 89%, 82%, 68% (Kaplan-Meier). The majority of the patients was in NYHA I-II at the end of the follow-up period. The majority of the early and late deaths were found to be myocardial in origin. The estimated surgical risk of the simultaneous procedures could be reduce by accepting of the severe surgical indications existing at this surgical field and with the availability of an experienced operating team.

[The state of heart transplantation in Hungary]. / A szívátültetés helyzete Magyarországon.

The first heart transplantation was performed in 1992 in Hungary. In the last nearly ten years 42 patients have got new heart. Among them 16 died. Authors discuss the changes of the surgical techniques and the postoperative treatment during this period, and what results were obtained with these new methods. They deal with problems, why so small number of the transplantations were performed. The causes of the death of the 16 patients were discussed.

[Coronary artery bypass grafting without extracorporeal circulation]. / Koszorúérmútétek extrakorporális keringés alkalmazása nélkül.

At the Department of Cardiovascular Surgery of Semmelweis University, Budapest we have performed 57 coronary bypass operations without using cardiopulmonary bypass between 1996 and September 2001. Due to the learning phase we preferred cases of 1-2 wessel diseases, and revascularisation necessary on the anterior surface of the heart. In the beginning the stabilization of the operative field was ensured by manual methods, then by applying mechanical stabilization devices (Octopus 2, Genzyme). As to the type of operative indication overwhelmingly elective operations were performed. REDO procedure, i.e. repeated coronary bypass operation was carried out in 2 cases. Forty-eight patients recovered without complication. Two patients died, one of them suffered perioperative infarction, the other died due to cerebral complication. Total mortality was 3.5%. As a consequence of cardiac ischaemia in the direct postoperative period, we performed emergent coronary ballon dilatation (PTCA) in two cases. In three cases we experienced perioperative infarction. We followed up our patients by way of interview and telephone interview. The follow-up is 95%, the average follow-up time is 15 months. Significant cardiac event (infarction, PTCA or REDO coronary operation) took place in the case of 7 patients. In the majority of our patients the operation resulted in an improvement of condition, 43 patients are free from angina.

[Atrial fibrillation after open-heart surgery--incidence, prevention and treatment]. / Posztoperatív pitvarfibrillàció okai, gyakorisága, megelözése és kezelése szívsebészeti betegeknél.

Atrial fibrillation is a common problem in the postoperative period following open-heart surgery. The pathogenesis of postoperative atrial fibrillation is likely to be multifactorial, however increased sympathetic activation may play a significant role. The aim of the study was to detect the incidence and possible reasons of atrial fibrillation in the first three postoperative days after open-heart surgery. Atrial fibrillation was detected in a total of 48 patients (mean age 64.8 +/- 8.8 years) of the 302 consecutive patients included in the study. The incidence of atrial fibrillation was 15.9%. In the history of patients with atrial fibrillation paroxysmal or persistent atrial fibrillation occurred in 18 cases. Acute ischaemia, hypopotassemia, high dose catecholamines contributed to the development of arrhythmias in 6, 4 and 4 cases, respectively. Lack of perioperative beta-blocker treatment was seen in 35 cases. Postoperative bleeding and reoperation occurred prior to the onset of atrial fibrillation in 9 instances. The applied antiarrhythmic therapy was metoprolol, amiodarone, propafenon and electrical cardioversion in 33, 21, 4 and 2 cases, respectively. Incidence of atrial fibrillation was found significantly lower in patients receiving beta-blocker premedication (13/181 [7.18%] versus 35/121 [28.9%]). There was no correlation between the incidence of atrial fibrillation and the length of the surgery, aortic-cross clamp time and the number of bypass grafts. Absence of preoperative beta-blocker treatment, previous atrial fibrillation and combined surgery were found to be strong predictors of atrial fibrillation. There was weaker association with increased age. On the basis of the outcome of our study beta-blocker premedication is suggested in most patients undergoing open-heart surgery.

Mutations in RAD3, MSH2, and RAD52 affect the rate of gene amplification in the yeast Saccharomyces cerevisiae.

We report here the use of the ADH4:CUP1 amplification detection system to identify five high amplification rate (HAR) strains of Saccharomyces cerevisiae that display 40- to 600-fold higher amplification rates than those of parental strains. We have identified a mutation in RAD3 DNA repair helicase gene in HAR strain B9-40 that results in a 40-fold increase in amplification rate. RAD3 is the functional homolog of the human XPD gene, suggesting that this model system will provide important candidates for genes that affect gene amplification in human cells. Isolation of the HAR strains has allowed us to test whether RAD52, which is essential for recombinational repair of DNA double-strand breaks, is also essential for amplification. Deletion of RAD52 in HAR strains B3-10 and B11-60 decreases amplification approximately 100-fold. In contrast, deletion of MSH2, which increases recombination between sequences with limited similarity, increases the amplification rate about 10-fold. These results suggest that recombination is an important step in amplification.

[Cardiovascular autonomic regulation following orthoptic heart transplantation]. / A cardiovascularis autonóm reguláció vizsgálata orthotopicus szívátültetést követóen.

Numerous recent observations have indicated autonomic reinnervation of transplanted human hearts. In order to assess autonomic regulation 5 patients were studied 1 to 5 years following cardiac transplantation. A series of tests were performed, including blood pressure and ECG recordings on rest, during 15/min patterned breathing, isometric handgrip exercise, and Valsalva manoeuvre. The time domain indices (SDRR, pNN50, rMSSD) and the frequency domain indices of heart rate variability were also studied. Among the five patients under study only one exhibited features compatible with both sympathetic and parasympathetic reinnervation. Traditional autonomic reflex tests and the analysis of time and frequency domain indices of HRV serve as simple tool in primary assessment of cardiac reinnervation.

[Anesthesia for heart transplantation]. / A szívátültetés anaesthesiája.

Heart transplantation, as a therapeutic possibility, has been available since 1992 in Hungary. The authors present the anaesthetic aspects and clinical experiences of this worldwide used therapeutic method. The specialties of the narcosis, the importance of the aseptic techniques, and the treatment of the denervated heart are emphasised.

[Total proximal reconstruction of chronic aortic dissection in patients with Marfan syndrome]. / Marfan-kóros betegeknél észlelt krónikus aorta dissectio teljes proximalis korrekciója.

Authors present two patients suffering from Marfan syndrome. Asymptomatically developed serious cardiovascular complications being characteristic of the syndrome itself were revealed at both cases. Type "A" aortic dissection was found at the first, and type "B" aortic dissection involving even the arch as well revealed at the other patient. They were operated on an elective base. Total proximal aortic reconstructions (aortic root-ascending aorta-arch) were performed under deep hypothermia using total circulatory arrest (35 and 87 min). Both patients are doing well without complaints 3-4 months following the surgical interventions. Control angiographic imagination has found normal anatomic conditions at one of the patients. Anastomosis stenosis at the borderline of the arch and descending aorta was revealed at the other case which should be necessary to operate at an later occasion.

[Traumatic rupture of the descending aorta]. / Az aorta descendens traumás eredetü rupturája.

During a ten-year period 16 patients were seen with aortic rupture and false aneurysm secondary to blunt trauma. One patient underwent an acute operation, 4 patients had operative therapy elective delayed and 11 patients were operated on for chronic traumatic false aneurysm. Operative delay was done in case of simultaneous multisystem injury (e.g. shock caused by abdominal injuries, cerebral contusion or pulmonary contusion on the right side). The shunt bypass method of repair was used in the case of 3 patients, cardiopulmonary bypass in 6 cases and simple aortic cross-clamping in 6 patients. One operation was performed without aortic cross-clamping. Primary repair was achieved in three patient, in 3 more cases a patch was inserted and in 9 cases interposition Dacron grafting was accomplished. One "wrapping" operation was performed. In 2 cases, reoperation was necessary because of postoperative bleeding. One patient died in the perioperative period. Right sided hemiparesis occurred in one patient postoperatively. Rupture does not affect the whole aortic wall, especially in young people because of the natural elasticity of vessel. The appearing shock and hypotension might protect the mediastinal pleura against bursting. This could provide a chance to survive. Our experience indicate: Elective delay of operation in patients with multiple system injuries can be achieved with antihypertensive therapy.

[Clinical importance of monophasic action potential registration in long QT syndrome]. / Monofázisos akciós potenciál regisztrálás klinikai jelentösége hosszú QT-szindrómában.

For more than 30 years, the monophasic action potential has been used as an experimental tool for the study of myocardial repolarisation. With recent improvements in catheter design, the utility of the tool as a means to identify the bases for ventricular arrhythmias in humans has been greatly improved. Abnormalities of repolarisation leading to ventricular arrhythmia formation can be identified and specific pharmacological therapies may be evaluated. The pathomechanism of major arrhythmias (ventricular tachycardia, ventricular fibrillation) occurring in long QT syndrome (LQTS) is not yet fully elucidated. The authors have recorded the monophasic action potentials (MAP) of the right ventricle in three patients with LQTS and with previous episodes of major ventricular arrhythmias. The changes in MAP duration and after depolarisation in response to spontaneous arrhythmias, programmed electrostimulation, atrial pacing and isoproterenol treatment were studied. In all of the three patients the early afterdepolarisation was present, which in two cases exhibited pause-dependent features. Thus in these patients dual chamber pacemaker implantatious were performed. These were the first permanent recordings of MAP during electrophysiological examination in Hungary and also the first evidences that the early afterdepolarisation does play a pathogenic role in the development of idiopathic LQTS. Further evaluation of the technique by cardiac electro-physiologists may improve both the diagnosis and the treatment of ventricular arrhythmias dependent upon afterdepolarisation formation.

[Echocardiographic diagnosis of intermittent failure of a mitral valve prosthesis]. / Intermittáló mitralis mübillentyü "beragadás" echocardiographiás diagnózisa.

Three cases are reported who had intermittent diastolic jamming of a mitral tilting disc valve. The clinical presentation of this unfrequent but catastrophic early postoperative complication was different in all cases: the first patient presented with heart failure, the third patient had loss of consciousness with enuresis and the second patient was asymptomatic at the time of the diagnosis. Electromechanical dissociation was first suspected by clinical examination in 2 cases but it was confirmed in all 3 cases by 2 dimensional and Doppler echocardiography. Transesophageal echocardiography did not provide any additional information. Besides opening failure of the valve Doppler echocardiography also demonstrated incomplete or delayed opening in the asymptomatic period. Survival is dependent on correct diagnosis and urgent surgical treatment of this type of prosthetic valve dysfunction.

[Experience with a transvenous pacemaker-cardioconverter-defibrillator without subcutaneous patch]. / Transzvénás, subcutan patch nélküli pacemaker-cardioverter-defibrillátorokkal szerzett tapasztalataink.

Sudden cardiac death caused by malignant ventricular arrhythmias is one of the main causes of cardiovascular mortality. Implantation of cardioverter-defibrillators has resulted in the reduction of the incidence of sudden cardiac death caused by malignant ventricular arrhythmias from the yearly 10-30% to 1%. For the very first time in Hungary, the authors applied only transvenous lead configuration for automatic cardioverter defibrillators in three patients. The indications of the implantation were ventricular fibrillation in one case, ventricular tachycardias refractory to drug treatment in two cases. Ventricular arrhythmias were secondary to coronary heart disease in two patients, dilatative cardiomyopathy in one patient. Preoperative, intraoperative and postoperative electrophysiological studies were regularly taken. Using Biotronik Phylax 03 device with a right ventricular electrode and a superior vena cava electrode and without subcutaneous patch the intraoperative defibrillation thresholds were 6, 11 and 12 J respectively. The fractally iridium coating increases the surface of the electrodes that has a very good effect on defibrillation threshold. During a mean follow-up of six months the occurring spontaneous ventricular arrhythmias (1 ventricular fibrillation and 5 ventricular tachycardias) were terminated by Phylax 03 with cardioversion-defibrillation or overdrive stimulation. The authors' results of intraoperative testing and clinical experiences show that the Phylax 03 biphasic system due to low defibrillation thresholds without subcutaneous patch can safely be applied with only transvenous implant technique in patients with major ventricular arrhythmias to prevent sudden cardiac death and to terminate ventricular tachycardia.