Is CYP2C Haplotype Relevant for Efficacy and Bleeding Risk in Clopidogrel-Treated Patients?

A recently discovered haplotype-CYP2C:TG-determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the CYP2C:TG haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (n = 283) treated with clopidogrel over 3-6 months were classified by CYP2C19 phenotype based on the CYP2C19*2*17 genotype, and based on the CYP2C19/CYP2C cluster genotype, and regarding carriage of the CYP2:TG haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2-14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6-20.5%). The incidence of ischemic events was similar in CYP2C:TG carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the CYP2C19/CYP2C cluster genotype or CYP2C:TG haplotype on the clinical efficacy/safety of clopidogrel.

Postoperative Hyperuricemia-A Risk Factor in Elective Cardiosurgical Patients.

Hyperuricemia is a well-known cardiovascular risk factor. The aim of our study was to investigate the connection between postoperative hyperuricemia and poor outcomes after elective cardiac surgery compared to patients without postoperative hyperuricemia. In this retrospective study, a total of 227 patients after elective cardiac surgery were divided into two groups: 42 patients with postoperative hyperuricemia (mean age 65.14 ± 8.9 years) and a second group of 185 patients without it (mean age 62.67 ± 7.45 years). The time spent on mechanical ventilation (hours) and in the intensive care unit (days) were taken as the primary outcome measures while the secondary measure comprised postoperative complications. The preoperative patient characteristics were similar. Most of the patients were men. The EuroSCORE value of assessing the risk was not different between the groups nor the comorbidities. Among the most common comorbidities was hypertension, seen in 66% of all patients (69% in patients with postoperative hyperuricemia and 63.7% in those without it). A group of patients with postoperative hyperuricemia had a prolonged time of treatment in the intensive care unit (p = 0.03), as well as a prolonged duration of mechanical ventilation (p < 0.01) and a significantly higher incidence of the following postoperative complications: circulatory instability and/or low cardiac output syndrome (LCOS) (χ2 = 4486, p < 0.01), renal failure and/or continuous venovenous hemodiafiltration (CVVHDF's) (χ2 = 10,241, p < 0.001), and mortality (χ2 = 5.22, p < 0.01). Compared to patients without postoperative hyperuricemia, elective cardiac patients with postoperative hyperuricemia have prolonged postoperative treatment in intensive care units, extended durations of mechanically assisted ventilation, and a higher incidence of postoperative circulatory instability, renal failure, and death.

Effects of trastuzumab and trastuzumab emtansine on corrected QT interval and left ventricular ejection fraction in patients with metastatic (HER2+) breast cancer.

BACKGROUND: Trastuzumab and trastuzumab emtansine are specific antibody and antibody-drug conjugates used in the treatment of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer. The aim of this study was to test their effect on the QTc interval duration and left ventricular ejection fraction (LVEF) in our patients, two parameters used in evaluation of cardiotoxicity. From May 2015 to October 2017, 26 patients with preserved LVEF were included in the study. All of them were previously treated with standard paclitaxel and cisplatin-based chemotherapy regimens. Electrocardiogram (ECG) was recorded just before each trastuzumab dose application and six months after the last dose. Echocardiography with LVEF measurement was performed several days before the application of the initial dose, and six months after the last cycle. Later, 24 patients with metastatic disease received additional treatment with trastuzumab emtansine after six months and the same ECG and echocardiography protocol was performed again. Due to reduction in LVEF, two patients were discontinued from additional treatment. RESULTS: A statistically significant QTc prolongation was found after each drug dose application, with an increase in mean QTc duration with every successive application, reaching the peak QTc values just before the fifth cycle of treatment. The QTc interval returned to its initial value six months after the last cycle (p < 0.001). These results were similar for both drugs. Mean LVEF before both treatment protocols was significantly higher compared to LVEF value after the treatment. LVEF before trastuzumab emtansine treatment was non-significantly higher than LVEF after trastuzumab treatment. CONCLUSION: Trastuzumab and trastuzumab emtansine cardiotoxicity manifested as a significant and progressive QTc prolongation after successive drug applications, reaching the peak value just before the fifth cycle of both drugs. Both medications also caused statistically significant but asymptomatic LVEF reduction. Complete reversibility of cardiotoxic effects of both drugs was confirmed by QTc interval and LVEF normalisation after the treatment discontinuation.

Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Peptide Therapy in the Heart Disturbances, Myocardial Infarction, Heart Failure, Pulmonary Hypertension, Arrhythmias, and Thrombosis Presentation.

In heart disturbances, stable gastric pentadecapeptide BPC 157 especial therapy effects combine the therapy of myocardial infarction, heart failure, pulmonary hypertension arrhythmias, and thrombosis prevention and reversal. The shared therapy effect occurred as part of its even larger cytoprotection (cardioprotection) therapy effect (direct epithelial cell protection; direct endothelium cell protection) that BPC 157 exerts as a novel cytoprotection mediator, which is native and stable in human gastric juice, as well as easily applicable. Accordingly, there is interaction with many molecular pathways, combining maintained endothelium function and maintained thrombocytes function, which counteracted thrombocytopenia in rats that underwent major vessel occlusion and deep vein thrombosis and counteracted thrombosis in all vascular studies; the coagulation pathways were not affected. These appeared as having modulatory effects on NO-system (NO-release, NOS-inhibition, NO-over-stimulation all affected), controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway and modulatory effects on the prostaglandins system (BPC 157 counteracted NSAIDs toxicity, counteracted bleeding, thrombocytopenia, and in particular, leaky gut syndrome). As an essential novelty noted in the vascular studies, there was the activation of the collateral pathways. This might be the upgrading of the minor vessel to take over the function of the disabled major vessel, competing with and counteracting the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels, compensating vessel occlusion and reestablishing the blood flow or bypassing the occluded or ruptured vessel. As a part of the counteraction of the severe vessel and multiorgan failure syndrome, counteracted were the brain, lung, liver, kidney, gastrointestinal lesions, and in particular, the counteraction of the heart arrhythmias and infarction.

Medication, nocturnal dipping profile and hypertensive emergency / Medicación, perfil de inmersión nocturna y emergencia hipertensiva

INTRODUCTION: the aim of this study was to analyze the medication used by the patients with hypertensive crisis (blood pressure above 180/120mmHg) and its impact on the main risk factors for hypertensive emergency development. METHODS: a total of 233 patients (108 male, 125 female), 184 had hypertensive urgency/ 53 emergency (54.44% /50.95% in women) at the Emergency department during 11 months. Patients were divided in five age groups as decades starting from the age of 40 (mean 65.85 years) and a total ten groups depending on which type of hypertensive medication they were using (ACEi, ARB, BB, CCB, diuretics, moxonidine, and their combinations). RESULTS: by using antihypertensive monotherapy percentage of hypertensive emergencies were 100.00%, 50.00%, 41.66%, 33.33%, 21.05%. Using ACEi + CCB + diuretic significantly decreased the number of emergencies to 0%, 18.47%, 21.05%, 25.00%, 33.33%; but adding beta blocker additionally diminished the risk. Overall 53 patients had no medication (22.75%) and 68 of 233 patients were smokers (29.18%, 63.23% male) of which 36 patients had hypertensive emergency (52.94% of smokers). The biggest number of non-dippers was found in patients who took ARBs, diuretics and/or CCB but the smallest number was shown in patients who took ACEi in combination with moxonidine (-20.07%). 22.02% of smokers were non-dippers (-54.67% nonsmokers). Odds ratio for getting hypertensive emergency in case patient had a non-dipper profile was 4.18 (CI 1.02 ­ 18.89, p < 0.05). Patients taking different medication (or none) did not have increased chance for hypertensive emergency development (OR 1.21, p = NS). We didn't find any differences in the non-dipping profile incidence between genders (72.12% males, 72.83% females). CONCLUSION: combinations of all antihypertensive medication showed benefit over monotherapy. Higher 24-hour and nighttime blood pressure (non-dipping profile) was significantly associated with greater change for developing hypertensive emergency.

INTRODUCCIÓN: el objetivo de este estudio fue analizar la medicación utilizada por los pacientes con crisis hipertensiva (presión arterial superior a 180/120mmHg) y su impacto en los principales factores de riesgo para el desarrollo de la emergencia hipertensiva. MÉTODOS: un total de 233 pacientes (108 hombres, 125 mujeres), 184 tenían urgencia hipertensiva/ 53 emergencia (54,44% /50,95% en mujeres) en el servicio de Urgencias durante 11 meses. Los pacientes fueron divididos en cinco grupos de edad según décadas a partir de los 40 años (media de 65,85 años) y un total de diez grupos según el tipo de medicación hipertensiva que utilizaban (IECA, ARA, BB, BCC, diuréticos, moxonidina y sus combinaciones). RESULTADOS: utilizando monoterapia antihipertensiva el porcentaje de urgencias hipertensivas fue del 100,00%, 50,00%, 41,66%, 33,33%, 21,05%. El uso de IECA + BCC + diuréticos disminuyó significativamente el número de urgencias al 0%, 18,47%, 21,05%, 25,00%, 33,33%; pero la adición de betabloqueantes disminuyó el riesgo. En general, 53 pacientes no tenían medicación (22,75%) y 68 de 233 pacientes eran fumadores (29,18%, 63,23% hombres), de los cuales 36 pacientes tuvieron una urgencia hipertensiva (52,94% de los fumadores). El mayor número de hipertensos no inmersivos se encontró en los pacientes que tomaban ARA, diuréticos y/o BCC, pero el menor número se mostró en los pacientes que tomaban IECA en combinación con moxonidina (-20,07%). El 22,02% de los fumadores no eran hipertensos inmersivos (-54,67% de los no fumadores). El odds ratio para obtener una emergencia hipertensiva en caso de que el paciente tuviera un perfil no inmersivo fue de 4,18 (IC 1,02 - 18,89, p < 0,05). Los pacientes que tomaban una medicación diferente (o ninguna) no tenían mayor probabilidad de desarrollar una emergencia hipertensiva (OR 1,21, p = NS). No se encontraron diferencias en la incidencia de perfil no inmersivo entre géneros (72,12% varones, 72,83% mujeres). CONCLUSIÓN: las combinaciones de toda la medicación antihipertensiva mostraron beneficios sobre la monoterapia. Una mayor presión arterial de 24 horas y nocturna (perfil de hipertensión no inmersiva) se asoció significativamente con un mayor cambio para desarrollar una emergencia hipertensiva.

Stable Gastric Pentadecapeptide BPC 157 May Counteract Myocardial Infarction Induced by Isoprenaline in Rats.

We revealed that the stable gastric pentadecapeptide BPC 157, a useful peptide therapy against isoprenaline myocardial infarction, as well as against isoprenaline myocardial reinfarction, may follow the counteraction of the recently described occlusion-like syndrome, induced peripherally and centrally, which was described for the first time in isoprenaline-treated rats. BPC 157 (10 ng/kg, 10 µg/kg i.p.), L-NAME (5 mg/kg i.p.), and L-arginine (200 mg/kg i.p.) were given alone or together at (i) 30 min before or, alternatively, (ii) at 5 min after isoprenaline (75 or 150 mg/kg s.c.). At 30 min after isoprenaline 75 mg/kg s.c., we noted an early multiorgan failure (brain, heart, lung, liver, kidney and gastrointestinal lesions), thrombosis, intracranial (superior sagittal sinus) hypertension, portal and caval hypertension, and aortal hypotension, in its full presentation (or attenuated by BPC 157 therapy (given at 5 min after isoprenaline) via activation of the azygos vein). Further, we studied isoprenaline (75 or 150 mg/kg s.c.) myocardial infarction (1 challenge) and reinfarction (isoprenaline at 0 h and 24 h, 2 challenges) in rats (assessed at the end of the subsequent 24 h period). BPC 157 reduced levels of all necrosis markers, CK, CK-MB, LDH, and cTnT, and attenuated gross (no visible infarcted area) and histological damage, ECG (no ST-T ischemic changes), and echocardiography (preservation of systolic left ventricular function) damage induced by isoprenaline. Its effect was associated with a significant decrease in oxidative stress parameters and likely maintained NO system function, providing that BPC 157 interacted with eNOS and COX2 gene expression in a particular way and counteracted the noxious effect of the NOS-blocker, L-NAME.

Diagnostic accuracy, sensitivity, and specificity of CT pulmonary artery to aorta diameter ratio in screening for pulmonary hypertension in end-stage COPD patients.

AIM: To determine the diagnostic accuracy of pulmonary artery to aorta ratio in screening for pulmonary hypertension in advanced chronic obstructive pulmonary disease (COPD) patients. METHODS: A prospective, diagnostic study was conducted in University Hospital Center Zagreb between January 2015 and March 2018. The study enrolled 100 patients who consecutively underwent chest computed tomography (CT), echocardiographic exam, and right heart catheterization. Two independent observers measured pulmonary artery and ascending aorta diameters. The correlation between the ratio and mean pulmonary artery pressure, measured invasively, was assessed. Patients with echocardiographic signs of moderate systolic or diastolic left ventricular dysfunction were excluded (n=44). RESULTS: Sixty-six patients (55.5% men), with a median age of 61, were identified. Median forced expiratory volume during the first second (FEV1) was 34±12, FEV1/forced vital capacity <0.70. Patients with and without pulmonary hypertension had pulmonary artery diameter of 36±7 mm and 27±4.6 mm, respectively (P<0.001). Median pulmonary artery/aorta (PA/A) ratios for patients with and without pulmonary hypertension were 1.05 and 0.81, respectively (P<0.001). PA/A ratio above 0.95 was an independent predictor of pulmonary hypertension with a specificity of 100% and a sensitivity of 74.51% (area under the curve=0.882; standard error=0.041; P<0.001). CONCLUSION: PA/A ratio as measured on chest CT images can be used as a screening tool instead of echocardiography.

Stable Gastric Pentadecapeptide BPC 157 Therapy for Monocrotaline-Induced Pulmonary Hypertension in Rats Leads to Prevention and Reversal.

Background. Monocrotaline selectively injures the lung's vascular endothelium and induces pulmonary arterial hypertension. The stable gastric pentadecapeptide BPC 157 acts as a prototype cytoprotective agent that maintains endothelium, and its application may be a novel therapy. Besides, BPC 157 prevents and reverses thrombosis formation, maintains platelet function, alleviates peripheral vascular occlusion disturbances, and has anti-arrhythmic and anti-inflammatory effects. Monocrotaline-induced pulmonary arterial hypertension in rats (wall thickness, total vessel area, heart frequency, QRS axis deviation, QT interval prolongation, increase in right ventricle systolic pressure and bodyweight loss) can be counteracted with early or delayed BPC 157 therapy. Methods and Results. After monocrotaline (80 mg/kg subcutaneously), BPC 157 (10 µg/kg or 10 ng/kg, days 1-14 or days 1-30 (early regimens), or days 14-30 (delayed regimen)) was given once daily intraperitoneally (last application 24 h before sacrifice) or continuously in drinking water until sacrifice (day 14 or 30). Without therapy, the outcome was the full monocrotaline syndrome, marked by right-side heart hypertrophy and massive thickening of the precapillary artery's smooth muscle layer, clinical deterioration, and sometimes death due to pulmonary hypertension and right-heart failure during the 4th week after monocrotaline injection. With all BPC 157 regimens, monocrotaline-induced pulmonary arterial hypertension (including all disturbed parameters) was counteracted, and consistent beneficial effects were documented during the whole course of the disease. Pulmonary hypertension was not even developed (early regimens) as quickly as the advanced pulmonary hypertension was rapidly attenuated and then completely eliminated (delayed regimen). Conclusions. Thus, pentadecapeptide BPC 157 prevents and counteracts monocrotaline-induced pulmonary arterial hypertension and cor pulmonale in rats.

Chronic kidney disease and cardiovascular mortality in patients with atrial fibrillation: European Society of Hypertension project - ESH A Fib.

ABSTRACT: Our aim was to analyze characteristics of atrial fibrillation (AF) patients with chronic kidney disease (CKD) from the Croatian cohort of the ESH A Fib survey and to determine the association of estimated glomerular filtration rate (eGFR) with cardiovascular (CV) mortality after 24 months of follow-up.Consecutive sample of 301 patients with AF were enrolled in the period 2014 to 2018. Hypertension was defined as BP > 140/90 mm Hg and/or antihypertensive drugs treatment, CKD was defined as eGFR (CKD Epi) < 60 ml/min/1.73 m2 which was confirmed after 3 months.CKD was diagnosed in 45.2% of patients (13.3% in CKD stage > 3b). CKD patients were older than non-CKD and had significantly more frequent coronary heart disease, heart failure and valvular disease. CKD patients had significantly higher CHA2DS2-VASc score and more CKD than non-CKD patients had CHA2DS2-VASc > 2. Crude CV mortality rate per 1000 population at the end of the first year of the follow-up was significantly higher in CKD vs non-CKD group who had shorter mean survival time. CV mortality was independently associated with eGFR, male gender, CHA2DS2VASc and R2CHA2DS2VASc scores.Prevalence of CKD, particularly more advanced stages of CKD, is very high in patients with AF. Observed higher CV mortality and shorter mean survival time in CKD patients could be explained with higher CHA2DS2VASc score which is a consequence of clustering of all score components in CKD patients. However, eGFR was independently associated with CV mortality. In our cohort, R2CHA2DS2VASc score was not associated significantly more with CV mortality than CHA2DS2VASc score.

The Role of Anxiolytics in Hypertensive Urgency Management.

Current guidelines do not cover hypertensive urgency management in out-of-hospital setting. Main goal of this study was to evaluate the value of anxiolytic therapy in hypertensive urgencies. We analyzed data gathered by out-of-hospital unit set up during one year. Arterial hypertension was the primary diagnosis in 178 (6.11%) patients, of whom 144 had hypertensive urgency with mean SBP reduction 19.5±7.2%; control group 10.1±6.9%. Anxiolytic therapy was administered in 60% of patients in hypertensive urgency group, and they had a statistically significant greater SBP reduction (p=0.03) than patients who did not receive anxiolytic therapy. There is a place for anxiolytic therapy in hypertensive urgency management.

Warfarin Dosing According to the Genotype-guided Algorithm is Most Beneficial in Patients With Atrial Fibrillation: A Randomized Parallel Group Trial.

BACKGROUND: Observational studies have indicated potential benefits of CYP2C9- and VKORC1-guided dosing of warfarin but randomized clinical trials have resulted in contradictory findings. One of the reasons for contradiction may be the negligence of possible differences between warfarin indications. This study aims to determine efficacy and safety of genotype-guided and clinically guided dosing of warfarin in atrial fibrillation (AF), deep-vein thrombosis (DVT), and pulmonary embolism (PE) within the first 5 days after the introduction of therapy. METHODS: In this single-center, single-blinded, randomized, controlled trial including patients of both sexes, ≥18 years of age, and diagnosed with AF, DVT, or PE, a total of 205 consecutive patients were allocated into the group where warfarin therapy was genotype-guided pharmacogenetics guided (PHG), and where it was adjusted according to the clinical parameters non pharmacogenetics guided (NPHG). Genotyping of CYP2C9*2, *3, and VKORC1 was performed using the real-time polymerase chain reaction method. The primary outcomes were the percentage of time in the therapeutic international normalized ratio (INR) (2.0-3.0) range and the percentage of patients who achieved a stable anticoagulation defined as the INR (2.0-3.0) range in at least 2 consecutive measurements. RESULTS: In patients with AF, the percentage of time spent in the therapeutic range of INR was higher in the PHG group [mean = 26% (SD 25.0)] than in the NPHG group [mean = 14% (SD 18.6)], [Δ = 12; 95% confidence interval, 0-23; P = 0.040]. There was no significant difference in other 2 indications for warfarin treatment. A stable dose of warfarin was achieved in a statistically higher number of patients in the PHG group 14/30 (47%) than in the NPHG group 7/32 (22%) (odds ratio = 3.13, 95% confidence interval, 0.92-10.98; P = 0.039). CONCLUSIONS: CYP2C9 and VKORC1 genotype-guided dosing of warfarin may be beneficial in patients diagnosed with AF. There is no evidence for such conclusion in patients with DVT and PE.

BPC 157 counteracts QTc prolongation induced by haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats.

AIM: Commonly, neuroleptics and prokinetics induce a prolonged QTc interval. In this study, stable gastric pentadecapeptide BPC 157 counteracts the prolongation of the QTc interval in Wistar rats that underwent daily administration of dopamine neuroleptics or prokinetics. Previously, in rats and mice, BPC 157 counteracted neuroleptic-induced catalepsy and gastric ulcers. MAIN METHODS: To counteract neuroleptic- or prokinetic-induced prolongation of the QTc interval, rats were given a BPC 157 regimen once daily over seven days (10µg, 10ng/kg ip) immediately after each administrations of haloperidol (0.625, 6.25, 12.5, and 25.0mg/kg ip), fluphenazine (0.5, 5.0mg/kg ip), clozapine (1.0, 10.0mg/kg ip), quetiapine (1.0, 10.0mg/kg ip), sulpiride (1.6, 16.0mg/kg ip), metoclopramide (2.5, 25.0mg/kg ip) or (1.0, 10.0mg/kg ip). Controls simultaneously received saline (5ml/kg ip). To assess the ECG presentation before and after neuroleptic/prokinetic medication, the assessment was at 1, 2, 3, 4, 5, 10, 15, 20 and 30min (first administration) as well as at 30min, 60min and 24h (first administration and subsequent administrations) and the ECG recording started prior to drug administration. KEY FINDINGS: Since very early, a prolonged QTc interval has been continually noted with haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats as a central common effect not seen with domperidone. Consistent counteraction appears with the stable gastric pentadecapeptide BPC 157. Thus, BPC 157 rapidly and permanently counteracts the QTc prolongation induced by neuroleptics and prokinetics. SIGNIFICANCE: Pentadecapeptide BPC 157 is suited for counteracting a prolonged QT interval.

Five-year angiographic and clinical follow-up of patients with drug-eluting stent implantation for symptomatic myocardial bridging in absence of coronary atherosclerotic disease.

OBJECTIVES: The objective of this study was to determine the long-term efficacy and dynamics of systolic and diastolic luminal changes within the bridged segments of coronary arteries after intracoronary stenting with drug-eluting stent (DES) in patients (pts) with symptomatic myocardial bridging (SMB) in the absence of coronary atherosclerosis. BACKGROUND: Although myocardial bridging (MB) represents a benign disease in the majority of pts, in its severest forms it is clinically manifested as typical or atypical angina, myocardial ischemia, myocardial infarction, left ventricular dysfunction, atrioventricular conduction disturbance, exercise-induced ventricular tachycardia, or sudden death. The only existing prospective study of 11 pts with SMB treated with bare-metal stent (BMS) reported a 36% in-stent restenosis (ISR) rate at 7 weeks repeated quantitative coronary angiography (QCA). METHODS: The study consisted of 15 consecutive patients (13 men and 2 women) with SMB of the mid-portion of the left anterior descending (LAD) coronary artery (and in 1 patient, concomitant MB of the left circumflex [LCX] coronary artery) and luminal diameter systolic narrowing of the tunneled segment of ≥50%, underwent percutaneous coronary intervention with DES. Clinical and non-invasive assessments of myocardial ischemia were determined every 6 months over 5 years and QCA was performed 12 and 24 months post procedure if not urged differently by deterioration of clinical symptoms and/or presence of positive ischemia tests. The minimal systolic and diastolic luminal diameters of the bridged/stented segments were measured before, immediately after, and 12 and 24 months post procedure by two independent observers blinded to each other's readings, using QCA commercial software. The endpoints of the study were ISR, target lesion revascularization (TLR) rate, in-stent diameter late luminal loss (LLL), and permanent disappearance or significant improvement of clinical symptoms. RESULTS: After 12 months, ISR and TLR in 16 treated vessels was 18.7%, LLL was 0.2 ± 0.6 mm and permanent disappearance or significant improvement of symptoms was achieved in all 15 pts. In 3 pts, clinically-driven repeat revascularization was necessary within the first 6 months. In 1 patient, coronary perforation complicated stent deployment and was immediately resolved by stent-graft implantation, followed by completely uneventful recovery. CONCLUSIONS: DES implantation in pts with SMB resistant to medical treatment results in prompt and long-term increase of systolic and diastolic luminal diameters, and long-lasting relief of clinical symptoms. Compared to BMS, stenting of SMB with DES resulted in significantly lower ISR and TLR rate.

Therapy for unhealed gastrocutaneous fistulas in rats as a model for analogous healing of persistent skin wounds and persistent gastric ulcers: stable gastric pentadecapeptide BPC 157, atropine, ranitidine, and omeprazole.

OBJECTIVE: This study focused on unhealed gastrocutaneous fistulas to resolve whether standard drugs that promote healing of gastric ulcers may simultaneously have the same effect on cutaneous wounds, and corticosteroid aggravation, and to demonstrate why peptides such as BPC 157 exhibit a greater healing effect. Therefore, with the fistulas therapy, we challenge the wound/growth factors theory of the analogous nonhealing of wounds and persistent gastric ulcers. METHODS: The healing rate of gastrocutaneous fistula in rat (2-mm-diameter stomach defect, 3-mm-diameter skin defect) validates macro/microscopically and biomechanically a direct skin wound/stomach ulcer relation, and identifies a potential therapy consisting of: (i) stable gastric pentadecapeptide BPC 157 [in drinking water (10 microg/kg) (12 ml/rat/day) or intraperitoneally (10 microg/kg, 10 ng/kg, 10 pg/kg)], (ii) atropine (10 mg/kg), ranitidine (50 mg/kg), and omeprazole (50 mg/kg), (iii) 6-alpha-methylprednisolone (1 mg/kg) [intraperitoneally, once daily, first application at 30 min following surgery; last 24 h before sacrifice (at postoperative days 1, 2, 3, 7, 14, and 21)]. RESULTS: Greater anti-ulcer potential and efficiency in wound healing compared with standard agents favor BPC 157, efficient in inflammatory bowel disease (PL-14736, Pliva), given in drinking water or intraperitoneally. Even after 6-alpha-methylprednisolone aggravation, BPC 157 promptly improves both skin and stomach mucosa healing, and closure of fistulas, with no leakage after up to 20 ml water intragastrically. Standard anti-ulcer agents, after a delay, improve firstly skin healing and then stomach mucosal healing, but not fistula leaking and bursting strength (except for atropine). CONCLUSION: We conclude that BPC 157 may resolve analogous nonhealing of wounds and persistent gastric ulcers better than standard agents.

Heart rate variability differences in post-myocardial infarction patients based on initial treatment during acute phase of disease.

The aim of study was to asses the heart rate variability (HRV) differences in 128 post-myocardial infarction (MI) patients based on initial treatment during acute phase of disease. The patients were divided into groups: group 1 patients who underwent primary PCI, group 2 patients who received fibrinolysis and group 3 patients who were treated conservatively. In comparison with groups 2 and 3, group 1 patients had all HRV analyzed parameters higher except for LF/HF ratio. The results of study suggest that patients who were treated by primary PCI had better preserved autonomic cardiac function compared with patients who received fibrinolysis or those who were treated conservatively in the acute phase of MI.

Early detection of left ventricular diastolic dysfunction in hypertensive heart disease by color Doppler myocardial imaging.

AIM: To determine if Color Doppler myocardial imaging could provide evidence of diastolic dysfunction in patients with hypertension whose pulse-wave Doppler parameters were normal. METHOD: The study included 33 patients (mean age 48+/-7.3 years) and a control group of 13 sex- and age-matched healthy individuals. Patients were divided into two groups according to mean blood pressure (BP) values during 24-hour blood pressure monitoring while under antihypertensive therapy: those with uncontrolled hypertension (n=22) and those with controlled hypertension (n=11). All study participants underwent complete standard echocardiography (2D, M-mode, pulsed and continuous Doppler) and a Color Doppler myocardial imaging study. RESULTS: Conventional Doppler parameters indicated relaxation disturbances in patients with uncontrolled hypertension, but were within a normal range in patients with controlled hypertension at baseline and follow-up. Parameters of global diastolic function measured by Color Doppler myocardial imaging revealed that E'/A', the ratio between E'-wave (early filling phase) and A'-wave (late diastolic wave due to atrial contraction), was <1 in 57% of segments at baseline in patients with uncontrolled hypertension, and did not significantly change at follow-up. In patients with controlled hypertension, E'/A'<1 was noted in 4.7% of segments at baseline and in 28.6% of segments at follow-up. CONCLUSION: Regional diastolic dysfunction measured by Color Doppler myocardial imaging was the first sign of myocardial dysfunction due to arterial hypertension, while the parameters of global diastolic dysfunction measured by conventional Doppler and Color Doppler myocardial imaging were still normal. Furthermore, in patients with uncontrolled hypertension with manifested global diastolic dysfunction, there was a change in late diastolic parameters. Our results point to a potentially important role of Color Doppler myocardial imaging in diagnosing hypertensive heart disease as well as in follow-up of treatment.

Doxorubicine-congestive heart failure-increased big endothelin-1 plasma concentration: reversal by amlodipine, losartan, and gastric pentadecapeptide BPC157 in rat and mouse.

Overall, doxorubicine-congestive heart failure (CHF) (male Wistar rats and NMRI mice; 6 challenges with doxorubicine (2.5 mg/kg, i.p.) throughout 15 days and then a 4-week-rest period) is consistently deteriorating throughout next 14 days, if not reversed or ameliorated by therapy (/kg per day): a stable gastric pentadecapeptide BPC157 (GEPPPGKPADDAGLV, MW 1419, promisingly studied for inflammatory bowel disease (Pliva; PL 10, PLD-116, PL 14736)) (10 microg, 10 ng), losartan (0.7 mg), amlodipine (0.07 mg), given intragastrically (i.g.) (once daily, rats) or in drinking water (mice). Assessed were big endothelin-1 (BET-1) and plasma enzyme levels (CK, MBCK, LDH, AST, ALT) before and after 14 days of therapy and clinical status (hypotension, increased heart rate and respiratory rate, and ascites) every 2 days. Controls (distilled water (5 ml/kg, i.g., once daily) or drinking water (2 ml/mouse per day) given throughout 14 days) exhibited additionally increased BET-1 and aggravated clinical status, while enzyme values maintained their initial increase. BPC157 (10 microg/kg) and amlodipine treatment reversed the increased BET-1 (rats, mice), AST, ALT, CK (rats, mice), and LDH (mice) values. BPC157 (10 ng/kg) and losartan opposed further increase of BET-1 (rats, mice). Losartan reduces AST, ALT, CK, and LDH serum values. BPC157 (10 ng/kg) reduces AST and ALT serum values. Clinical status of CHF-rats and -mice is accordingly improved by the BPC157 regimens and amlodipine.

Pentadecapeptide BPC 157 attenuates chronic amphetamine-induced behavior disturbances.

AIM: To investigate the effect of pentadecapeptide BPC 157 on chronic exposure to amphetamine in rats, particularly the changes commonly referred in chronic amphetamine studies as tolerance (lesser grade of stereotyped behavior, without increased excitability) and reverse tolerance (ie, prominent stereotyped behavior and heightened startle response upon late amphetamine challenges). METHODS: After initial application (initial single dose-regimen), amphetamine (10 mg/kg,ip) was given once daily till d 5 (continuous administration-regimen), and thereafter on d 8, 16, and 46 (intermittent administration regimen). Fo r stereotyped behavior and heightened startle response the observation period was 120 min after amphetamine application, and each animal was observed for 10 s in 5 min intervals. Pentadecapeptide BPC 157 (10 microg/kg or 10 ng/k g, ip) or saline (5.0 mL/kg, ip) were given only at the beginning of the experiment, simultaneously with the initial dose of amphetamine. RESULTS: In relation to applied initial-single/continuous/intermittent amphetamine applications regimen, the control amphetamine rats throughout the experiment showed the changes in stereotyped behavior and heightened startle response, increment or decrement, commonly explained in chronic amphetamine studies as tolerance and reverse tolerance. After t he initial application of the amphetamine, the higher BPC 157 dosage apparently attenuated the stereotyped behavior, while the lower dosage of BPC 157 did not reach a statistical significance. Considering the forthcoming amphetamine challenges, in the rats initially treated with pentadecapeptide BPC 157, either 10 microg- or 10 ng-dose, at the time of the first application of amphetamine, the stereotyped behavior remains to be attenuated after all additional amphetamine challenges (on d 2-5, 8, 16, and 46). This attenuation was not limited to stereotyped behavior only. After the initial application of the amphetamine the heighten ed startle response was also apparently mitigated in rats receiving the BPC 157 dosage, either higher or lower. Later, confronted with the forthcoming amphetamine challenges, they showed apparently less abnormal excitability at all tested points. CONCLUSION: In summary, gastric pentadecapeptide BPC 157 (ie, both microg- and ng-BPC 157 regimens) attenuated chronic amphetamine disturbances. This effect was present throughout the observation period at a statistically significant level. Therefore, it seems that this gastric pentadecapeptide BPC 157 has a modulatory effect on dopamine system, and it could be used in chronic amphetamine disturbances.