Thrombolytic effect of Siddha herbal formulation Sikkanjar Manapagu using in-Silico model

Background: Thromboembolic disorders are one of the important causes leading to death. In the Siddha system of medicine, many drugs have been mentioned in the literature and their thrombolytic potential needs to be scientifically evaluated. Aim: The study aims to perform the In Silico computational studies of Phytoconstituents of Siddha formulation Sikkanjar Manapagu (SM) to evaluate its thrombolytic potential. Methods: Autodock program was used for the molecular docking studies of the retrieved phytoconstituents such as Zingiberene, Gingerenone-A, 6 Gingerol of Zingiber officinale, Menthol, Luteolin, Citronellol of Mentha arvensis, Eugenol, Limonene, Myrcene, and Linalool of Citrus aurantium against target protein Human Plasminogen Activation Loop Peptide - PDB 4DCB. Results: A total of ten compounds were screened, of these Zingiberene, Menthol, Citronellol, Eugenol, Limonene, Myrcene, and Linalool showed high binding against active amino acid residue 195. Conclusion: Based on further experiments and clinical trials, the formulation Sikkanjar Manapagu could be proved to be effective in thrombolytic treatment.

Induced pluripotent stem cells can improve thrombolytic effect of low-dose rt-PA after acute carotid thrombosis in rat

Background Intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is the standard treatment for acute ischemic stroke. Standard-dose rt-PA (0.9 mg/kg) is known to achieve good recanalization but carries a high bleeding risk. Lower dose of rt-PA has less bleeding risk but carries a high re-occlusion rate. We investigate if induced pluripotent stem cells (iPSCs) can improve the thrombolytic effect of low-dose rt-PA (0.45 mg/kg). Methods Single irradiation with 6 mW/cm2 light-emitting diode (LED) for 4 h at rat common carotid artery was used as thrombosis model according to our previous report. Endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), and interleukin 1 beta (IL-1 beta) were used as the inflammatory markers for artery endothelial injury. Angiopoietin-2 (AP-2), brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were examined in artery wall and iPSCs culture. Animal ultrasound was used to evaluate the stenosis degree of common carotid artery before and at 2 h, 24 h, 4 days and 7 days after LED irradiation. Results After LED irradiation alone, there was a persistent occlusion from 2 h to 7 days. Standard-dose rt-PA alone could recanalize the occluded artery from 24 h to 7 days to stenotic degree ≤ 50%. Low-dose rt-PA or 1 × 106 mouse iPSCs alone could not recanalize the occluded arteries from 2 h to 7 days. Combination use of low-dose rt-PA plus 1 × 106 mouse iPSCs caused better recanalization from 24 h to 7 days. ET-1, ICAM-1 and IL-1 beta were strongly expressed after LED irradiation but reduced after iPSCs treatment. AP-2, BDNF and VEGF were rarely induced after LED irradiation but strongly expressed after iPSCs treatment. In vitro study showed iPSCs could express AP-2, BDNF and VEGF. Conclusion The adjuvant use of iPSCs may help improving the thrombolytic effect of low-dose rt-PA by suppressing inflammatory factors and inducing angiogenic trophic factors. Stem cells could be a potential regimen in acute thrombolytic therapy to improve recanalization and reduce complications.

The Value of Electrocardiographic Changes in Evaluating the Prognosis of Acute ST-Elevation Myocardial Infarction (STEMI) After PCI

To explore the relationship between the changes of ECG indexes and the prognosis after PCI in patients with acute ST-elevation myocardial infarction (STEMI), and to develop the evaluation method and analyze the advantages and characteristics. 420 patients with acute myocardial infarction (AMI) were admitted to our hospital from March 2017 to April 2020. They were divided into the observation group (ST segment elevation type) with 220 patients and control group (non-ST segment elevation type) with 200 patients according to whether ST segment elevation was or not. ECG was detected before and 1 hour after operation, evaluation of thrombolytic effect, 6-minute walking test and echocardiography were performed 3 months after operation. Compared with the control group, the ECG of the observation group showed St Compared with the control group, the thrombolytic effect of the observation group was significantly improved, and the difference was statistically significant (P < 0.05); compared with the control group, the thrombolysis effect of the observation group was significantly improved, the difference was statistically significant (P < 0.05); ECG index can effectively reflect the recovery of cardiac function after PCI in patients with acute STEMI, and can effectively indicate the improvement of symptoms in patients with AMI, which is worthy of clinical application.

Selective sphingosine 1-phosphate receptor 1 modulation augments thrombolysis of low-dose tissue plasminogen activator following cerebrovascular thrombosis

BackgroundResults from our recent study demonstrate that sphingosine-1-phosphate receptor 1 (S1PR1) modulation improves microvascular hemodynamics after cerebrovascular thrombosis. This study was to determine the microvascular hemodynamic effects of sub-thrombolytic dose of tPA combined with a selective S1PR1 modulator ozanimod in a mouse model of cerebrovascular thrombosis.MethodsMicrovascular circulation in mice was monitored in vivo by two-photon microscopy. Thrombosis was induced in cortical arterioles by laser irradiation. Arteriolar flow velocity was measured by line-scanning following plasma-labeling with fluorescein-dextran.ResultsLaser-induced thrombosis led to a persistent reduction of flow velocity in cortical arterioles. Sub-thrombolytic dose of tPA along with vehicle control did not improve the flow velocity in cortical arterioles following thrombosis. In contrast, sub-thrombolytic dose of tPA along with ozanimod dramatically restored flow velocity in cortical arterioles following thrombosis. Ozanimod did not affect coagulation and bleeding time. Notably, ozanimod reduced thrombus volume without altering microvascular lumen diameter. In addition, ozanimod reduced leukocyte components within the thrombus.ConclutionsThese findings demonstrate that the thrombolytic effect of sub-thrombolytic dose of tPA is markedly enhanced by S1PR1 modulation, implying that S1PR1 modulation may improve the therapeutic benefit of low-dose tPA in patients with acute ischemic stroke.

Levels of Fibrin Degradation Products at Admission With Acute Ischemic Stroke Correlate With the NIH Stroke Scale Score 1 h After Intravenous Thrombolysis

Background: Fibrin degradation products (FDPs) are fragments released by the plasmin-mediated degradation of fibrinogen or fibrin. Whether plasma levels of these fragments can predict the thrombolytic effect of recombinant tissue plasminogen activator (r-tPA) remains unknown.Methods: We performed a hospital-based study of patients with acute ischemic stroke (AIS) to explore the relationship between FDP levels at admission and the NIH Stroke Scale (NIHSS) score 1 h after thrombolysis treatment. In this retrospective, single-center study, the data of all patients with AIS who received r-tPA treatment at Beijing Tiantan Hospital from January 2019 to October 2020 were collected and analyzed. Demographic and clinical data, including laboratory examinations, were also analyzed.Results: A total of 339 patients with AIS were included in this study. Of these, 151 showed favorable effects of r-tPA, and 188 showed unsatisfactory effects at 1 h after thrombolysis. Overall, we found an inverse relationship between the FDPs levels at admission and the NIHSS score. A significant difference was observed when using the interquartile range of the FDPs levels (1.31 μg/mL) as a cutoff value (P = 0.003, odds ratio [OR] = 1.95, 95% confidence interval [CI]: 1.26–3.01), even after adjusting for confounding factors (P = 0.003, OR = 2.23, 95% CI: 1.31–3.77). In addition, significant associations were observed in the tertile (T3) and quartile (Q3, Q4) FDP levels when compared with T1 or Q1. A nomogram was also employed to create a model to predict an unsatisfactory effect of r-tPA. We found that FDP levels, white blood cell count, age, D-dimer level, and body mass index could influence the thrombolytic effect of r-tPA.Conclusion: In conclusion, the present study demonstrated that the levels of FDPs at admission can be used as a prognostic factor to predict the curative effect of r-tPA.

Clinical observation of thrombolytic effect of alteplase combined with butylphthalide in patients with acute anterior circulation cerebral infarction

Objective: This study aims to evaluate the clinical effect of alteplase combined with butylphthalide in treating patients with acute anterior circulation cerebral infarction. Methods: Retrospective study methods were used. Eighty patient cases with acute anterior circulation cerebral infarction treated in Baoding First Central Hospital, China from January 2018 to December 2020 were randomly and averagely divided into two groups. Patients in the two groups were given symptomatic treatment. Patients in the experimental group were treated with alteplase combined with butylphthalide for thrombolytic therapy, whereas patients in the control group were treated with urokinase thrombolytic therapy. The NIHSS score, effective rates and neurological function recovery were analysed one day, seven days and 30 days after treatment were analyzed, respectively. So as the incidence of adverse reactions within seven days after drug adminutesistration. Results: The NIHSS scores of the two groups were significantly lower than those before treatment on one day, seven days and 30 days after treatment (experimental group, p=0.00; control group, p=0.02). The experimental group was more significantly lower than the control group (p=0.00). The effective rate of the experimental group was significantly higher than that of the control group (p=0.03), and the recovery rate after treatment was significantly higher than that of the control group (p=0.04). Within one week after treatment, the complication rate was 15% in the experimental group and 20% in the control group but was not significantly different (p=0.56). Conclusion: Alteplase combined with butylphthalide is effective and safe in the treatment of acute anterior circulation cerebral infarction without obvious complications. doi: https://doi.org/10.12669/pjms.37.4.3986 How to cite this:Qi FX, Hu Y, Wang S. Clinical observation of thrombolytic effect of alteplase combined with butylphthalide in patients with acute anterior circulation cerebral infarction. Pak J Med Sci. 2021;37(4):---------. doi: https://doi.org/10.12669/pjms.37.4.3986 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Lysis of arterial thrombi by perfusion of N,N’-Diacetyl-L-cystine (DiNAC)

The search persists for a safe and effective agent to lyse arterial thrombi in the event of acute heart attacks or strokes due to thrombotic occlusion. The culpable thrombi are composed either primarily of platelets and von Willebrand Factor (VWF), or polymerized fibrin, depending on the mechanism of formation. Current thrombolytics were designed to target red fibrin-rich clots, but may be not be efficacious on white VWF-platelet-rich arterial thrombi. We have developed an in vitro system to study the efficacy of known and proposed thrombolytic agents on white clots formed from whole blood in a stenosis with arterial conditions. The agents and adjuncts tested were tPA, ADAMTS-13, abciximab, N-acetyl cysteine, and N,N’-Diacetyl-L-cystine (DiNAC). Most of the agents, including tPA, had little thrombolytic effect on the white clots. In contrast, perfusion of DiNAC lysed thrombi as quickly as 1.5 min, which ranged up to 30 min at lower concentrations, and resulted in an average reduction in surface area of 71 ± 20%. The clot burden was significantly reduced compared to both tPA and a saline control (p<0.0001). We also tested the efficacy of all agents on red fibrinous clots formed in stagnant conditions. DiNAC did not lyse red clots, whereas tPA significantly lysed red clot over 48 h (p<0.01). These results lead to a novel use for DiNAC as a possible thrombolytic agent against acute arterial occlusions that could mitigate the risk of hyper-fibrinolytic bleeding.

The Thrombolytic and Cytotoxic Effects of Nigella sativa (L.) Seeds: The Prophetic Medicine

The Water-Soluble Extract (WSE) is a crude bioactive phytoconstituent of Nigella sativa (L.) seeds discovered recently. The current findings report about the thrombolytic and cytotoxic effects of WSE using human blood clot lysis and brine shrimp lethality (BSL) bioassay. The thrombolytic effect of WSE (1,666.67 µg/mL) was determined via the clot and lysate weight measurements compared to streptokinase (STK) of 30,000 IU/mL and normal saline (NS) while the cytotoxicity of WSE (44.14-2,000 µg/mL) against vincristine sulfate (VCS;3.125-100 µg/mL). WSE has shown extremely statistically significant (p<0.0001) clot lysis (90.00%) compared to NS (3.76%) whilst it was also significantly different (p<0.0063) to STK (72.41%) exhibiting LC50 of 1,795.90 µg/mL vs. VCS (39.25 µg/mL) in a dose-dependent manner. The current results suggested WSE has a potent thrombolytic effect with mild dose-dependent cytotoxicity towards brine shrimp nauplii (Artemia salina). It also suggested WSE might have enzymatic roles on thrombin, fibrin, and plasmin of blood. This pharmacological action of WSE is might be due to its antioxidant property, short-chain fatty acids and/or amino acids. Further studies are highly recommended on the enzymatic role(s) and bioactive phytoconstituents of WSE.

The oral thrombolysis for venous thrombosis (clinical trial)

Введение. Таргетная терапия тромбозов заключается в тромболитической терапии. В настоящий момент в подавляющем большинстве случаев терапия тромбозов у пациента сводится к назначению антикоагулянтов в расчете на механизм собственного фибринолиза/тромболизиса. Применение активаторов плазминогена эффективно, но сопряжено с опасностью тяжелых кровотечений и проводится только в условиях стационара. Очень перспективно для лечения тромбозов выглядит применение лекарственных препаратов на основе иммобилизированных субтилизинов, которые имеют прямое тромболитическое действие при пероральном приеме. В России зарегистрирован лекарственный препарат на основе иммобилизированных субтилизинов Тромбовазим, который имеет показание лечение хронической венозной недостаточности. Основой фармакодинамики препарата является тромболитическое действие. Цель исследования: показать, что включение лекарственного препарата Тромбовазим в комплексную терапию тромбозов венозного русла нижних конечностей улучшает результаты лечения. Материалы и методы. Проведено многоцентровое рандомизированное плацебоконтролируемое двойное слепое клиническое исследование. В настоящий момент лекарственный препарат Тромбовазим зарегистрирован к медицинскому применению в дозе 1600 ЕД/сут. Клиническое исследование было проведено по двум протоколам: Протокол 1 включение Тромбовазима в комплексную терапию тромбоза в суточной дозе 1600 ЕД Протокол 2 включение Тромбовазима в комплексную терапию тромбоза в более высоких дозах 3200 и 4800 ЕД/сут. Результаты. У пациентов, принимающих лекарственный препарат Тромбовазим в дозе 1600 3200 ЕД/сут, увеличение кровотока либо реканализацию вены наблюдали в 1,6 раза чаще (на 60 больше), чем среди пациентов, получающих плацебо. Эффективная тромболитическая доза препарата Тромбовазим 1600 3200 ЕД/сут. Заключение. Лекарственный препарат на основе иммобилизированных субтилизинов Тромбовазим обладает тромболитическим действием при пероральном применении. Тромбовазим в составе комплексной терапии больных с тромбозом венозных сосудов быстро восстанавливает кровоток в зоне скомпрометированного кровообращения. Introduction. The target therapy of thrombosis consists of thrombolytic therapy. At present in most of cases, the therapy of thromboses in patient is reduced to the prescribing of anticoagulants based on mechanism of own fibrinolysis/thrombolysis. The use of plasminogen activators is effective, but is associated with the risk of severe bleeding and is carried out only in hospital. The administration of drugs that based on immobilized subtilisins looks very promising for thromboses treatment. The immobilized subtilisins have a direct thrombolytic effect under oral administration. The drug Trombovazim is based on immobilized subtilisins and has been registered in Russia. Trombovazim has an indication treatment of chronic venous insufficiency thrombolytic action is the basis of its pharmacodynamics. Aim: to show that Trombovazim in complex therapy of venous thromboses of the lower extremities improves the treatment outcomes. Materials and methods. A multicenter randomized doubleblind placebocontrolled clinical trial was carried out. At present Trombovazim is registered for medical use at a dose of 1600 U/day. The clinical study was undertaken according to 2 protocols: Рrotocol 1 Trombovazim inclusion in complex therapy of thrombosis at a dose of 1600 U/day Рrotocol 2 Trombovazim inclusion in complex therapy of thrombosis in higher doses 3200 and 4800 U/day. Results. In patients taking Trombovazim at a dose of 1600 3200 U/day increased blood flow or vein recanalization was observed 1.6 times more often (60 more) than in patients receiving placebo. The effective thrombolytic dose of Trombovazim is 1600 3200 U/day. Conclusion. Trombovazim has a thrombolytic action under oral administration. Thrombovazim in complex therapy of patients with venous thrombosis quickly restores the blood flow in a zone of compromised blood circulation.