Reteplase 10unit powder and solvent for solution for injection vials

Objective To systematically compare the benefits and risks of all thrombolytic agents (tenecteplase, reteplase, and alteplase) at different doses for thrombolytic therapy in patients with acute ischemic stroke (AIS). Background Alteplase is the cornerstone treatment for AIS, but alternative thrombolytic agents are needed. The efficacy and safety of tenecteplase and reteplase, compared to alteplase, remain unclear, as does the optimal dosing for these treatments. Method A systematic search was conducted in PubMed, Web of Science, SCOPUS, and the Cochrane Central Register of Controlled Trials (CENTRAL) for relevant English-language studies up to July 5, 2024. Randomized controlled trials (RCTs) comparing standard-dose alteplase with varying doses of tenecteplase or reteplase in AIS patients were included. Primary outcomes were functional outcome at 90 days, symptomatic intracranial hemorrhage, death within 90 days, and serious adverse events. Data on study characteristics, patient demographics, interventions, and outcomes were extracted, and bias risk assessed. A multivariate random-effects model was used for network meta-analysis to derive odds ratios (OR) and 95% confidence intervals (CI). Result Twelve RCTs were included (10 with tenecteplase, 2 with reteplase) involving 6,633 patients, all compared against 0.9 mg/kg alteplase. In comparison with alteplase, tenecteplase demonstrated OR of 1.08 for achieving an excellent functional outcome at 90 days (95% CI: 0.97 to 1.22, P = 0.17). Reteplase, on the other hand, showed a significantly higher OR of 1.55 for the same outcome (95% CI: 1.23 to 1.95, P = 0.0002). Reteplase at 18 mg + 18 mg (OR 1.6, 95% CI: 0.91–2.5) showed a higher probability of achieving an excellent functional outcome at 90 days compared to alteplase. When considering a good functional outcome at 90 days, tenecteplase had an OR of 1.03 (95% CI: 0.81 to 1.3, P = 0.82), while reteplase had an OR of 1.15 (95% CI: 0.61 to 2.19, P = 0.66). Tenecteplase at 0.25 mg/kg (OR 1.3, 95% CI: 0.79–2.5) had the highest probability of achieving a good functional outcome at 90 days. For safety outcomes, 0.25 mg/kg tenecteplase had lower incidences of symptomatic intracranial hemorrhage (OR 0.88, 95% CI: 0.35–1.8), death within 90 days (OR 0.91, 95% CI: 0.54–1.4), and serious adverse events (OR 1.0, 95% CI: 0.47–2.3) compared to alteplase, though differences were not statistically significant. Reteplase at 18 mg + 18 mg had higher incidences of death within 90 days (OR 1.2, 95% CI: 0.48–3) and serious adverse events (OR 1.4, 95% CI: 0.4–5.0) compared to alteplase, without significant differences. Subgroup analysis showed better efficacy with 0.25 mg/kg tenecteplase in Asians (OR 1.18, 95% CI 0.96–1.45, P = 0.12) than in Caucasians (OR 1.08, 95% CI 0.9–1.3, P = 0.39). Conclusion This study suggests that tenecteplase and reteplase are viable alternatives to alteplase for thrombolysis in AIS. Tenecteplase at 0.25 mg/kg and reteplase at 18 mg + 18 mg may offer better efficacy compared to standard-dose alteplase, although the risk of adverse events with reteplase should be considered. Tenecteplase at 0.25 mg/kg appears to provide the best benefit-risk profile based on current evidence. Further head-to-head trials of tenecteplase and reteplase are needed to determine the optimal thrombolytic agent and dosing. Systematic review registration https://www.crd.york.ac.uk/prospero/ , PROSPERO CRD42024566146.

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BACKGROUND: Currently, there is limited evidence on the efficacy and safety of various thrombolytic drugs at different dosages for the treatment of acute ischemic stroke (AIS). From current randomized clinical trials, the optimal type and dosage of thrombolytics for patients with AIS are unclear. METHODS: This systematic review was registered in PROSPERO (CRD42024563757). We searched four databases using a combination of keywords that contained various intravenous thrombolytics, as well as acute ischemic stroke. Only data from participants with AIS treated with various intravenous thrombolytics within the 4.5-h time window were included. Among initially identified studies, 16 met the selection criteria. Network meta-analysis was conducted for efficacy (90 day modified Rankin scale score) and safety (intracranial hemorrhage events, mortality at 90 days) using Stata 17.0 software, with a fixed-effects model. Cochrane risk of bias tool assessed all risk of bias domains, and the CINeMA Evidence Assessment Tool evaluated the level of evidence for each outcome. RESULTS: A total of 9056 studies were retrieved through the literature search, and 12,792 patients screened from 16 randomized controlled trials were included in the network meta-analysis. The risk of bias in the included studies ranged from moderate to low. The network meta-analysis results indicated that reteplase at 18 + 18 mg ranked highest in efficacy, though its safety was lower compared to 0.25 mg/kg tenecteplase and alteplase. The dose of 0.25 mg/kg tenecteplase emerged as the optimal dose, demonstrating both superior efficacy and a lower risk of bleeding compared to alteplase, making it a potential alternative to alteplase. The dose of 50 mg prourokinase was associated with the highest risk of symptomatic intracranial hemorrhage and was inferior to reteplase in terms of both efficacy and safety. The CINeMA Evidence Assessment Tool identified one outcome with a high level of evidence, several with moderate levels, and the remainder with low levels. CONCLUSIONS: Reteplase at 18 + 18 mg may be more suitable for patients with lower incidence of adverse events evaluated by physicians. Compared to 0.9 mg/kg alteplase, 0.25 mg/kg tenecteplase is more effective, with the lowest risk of intracranial hemorrhage. However, as tenecteplase's dosages increase (0.32 mg/kg and 0.4 mg/kg), its efficacy in improving neurological deficits decreases, while the risk of intracranial hemorrhage and death (especially at 0.4 mg/kg) increases. Clinicians are supposed to carefully assess the needs of patients with AIS and the risks then choose decent thrombolytics.

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BackgroundIntravenous thrombolytics are essential for achieving timely reperfusion in acute ischemic stroke (AIS), with alteplase historically serving as the standard of care. Emerging alternatives like recombinant human prourokinase (rhPro-UK), reteplase, and tenecteplase offer potential improvements in efficacy, safety, and convenience, necessitating a comparative analysis.MethodsElectronic databases, including PubMed, ScienceDirect, and Cochrane Central, were comprehensively searched from inception till December 2024 for relevant studies. A frequentist network meta-analysis was performed using R software version 4.2.3, and the "netmeta" package was employed. Alteplase 0.9 mg served as the reference group, with P-scores employed to determine the relative rankings of various interventions. The risk of publication bias was evaluated through funnel plots and Egger's regression test.ResultsEighteen trials with 12,950 participants were included in the final analysis. Compared to alteplase 0.9 mg, excellent functional outcome (mRS 0-1) was significantly improved by Reteplase 18 + 18 mg (RR = 1.13, p < 0.01) and Tenecteplase (TNK) 0.25 mg (RR = 1.05, p < 0.01). For a good functional outcome (mRS 0-2), Reteplase 18 + 18 mg (RR = 1.06, p < 0.01) and TNK 0.32 mg (RR = 1.30, p < 0.01) were significantly more effective than alteplase. Safety outcomes, symptomatic intracranial hemorrhage (sICH), and mortality were not significantly different between alteplase and other thrombolytics. According to P-scores, Reteplase 18 + 18 mg ranked the best for excellent functional outcome (P-score = 0.89) and TNK 0.32 mg for good functional outcome (P-score = 0.99), while rhPro-UK 35 mg ranked the best for sICH (P-score = 0.89).ConclusionReteplase 18 + 18 mg and TNK 0.32 mg demonstrated superior functional outcomes compared to alteplase, while rhPro-UK 35 mg showed the best safety profile with the lowest sICH risk.

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BACKGROUND AND PURPOSE: Reteplase is the third generation of alternative thrombolytic agent. We hypothesis that reteplase will be non-inferior to alteplase in achieving excellent functional outcome at 90 days among eligible patients with acute ischaemic stroke. METHODS AND DESIGN: Reteplase versus alteplase for acute ischaemic stroke within 4.5 hours (RAISE) trial is a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE), controlled phase 3 non-inferiority trial. A total of 1412 eligible patients will be randomly assigned to receive either reteplase at a dose of 18 mg+ 18 mg or alteplase 0.9 mg/kg at a ratio of 1:1. An independent data monitoring committee will review the trail's progress and safety data. STUDY OUTCOMES: The primary efficacy outcome of this study is proportion of individuals attaining an excellent functional outcome, defined as modified Rankin Scale (mRS) 0-1 at 90 days. The secondary efficacy outcomes encompass favourable functional outcome defined as mRS 0-2, major neurological improvement on the National Institutes of Health Stroke Scale, ordinal distribution of mRS and Barthel Index score of at least 95 points at 90 days. The primary safety outcomes are symptomatic intracranial haemorrhage at 36 hours within 90 days. DISCUSSION: The RAISE trial will provide crucial insights into the selection of thrombolytic agents for stroke thrombolysis. TRIAL REGISTRATION NUMBER: NCT05295173.

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We performed molecular dynamics simulations of Reteplase in the presence of different excipients to study the stabilizing mechanisms and to identify the role of excipients during freeze drying. To simulate the freeze-drying process, we divided the process into five distinct steps: (i) protein-excipient formulations at room temperature, (ii) the ice-growth process, (iii)-(iv) the partially solvated and fully dried formulations, and (v) the reconstitution. Furthermore, coarse-grained (CG) simulations were employed to explore the protein-aggregation process in the presence of arginine. By using a coarse-grained representation, we could observe the collective behavior and interactions between protein molecules during the aggregation process. The CG simulations revealed that the presence of arginine prevented intermolecular interactions of the catalytic domain of Reteplase, thus reducing the aggregation propensity. This suggests that arginine played a stabilizing role by interacting with protein-specific regions. From the freeze-drying simulations, we could identify several protein-specific events: (i) collapse of the domain structure, (ii) recovery of the drying-induced damages during reconstitution, and (iii) stabilization of the local aggregation-prone region via direct interactions with excipients. Complementary to the simulations, we employed nanoDSF, size-exclusion chromatography, and CD spectroscopy to investigate the effect of the freeze-drying process on the protein structure and stability.

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Background: ). However, the role different factors in its expresssin rate remained to be elucidated. Objectives: Optical cell density (OD), IPTG concentration, and expression time are highly effective in the protein expression rates. Therefore, we aimed to determine the optimum levels of these factors for reteplase expression using response surface methodology (RSM). Materials and Methods: BL21 strain. Induction of expression was done by IPTG and analyzed by the SDS page. experiments were designed using the RMS, while the effects of different conditions were evaluated using the Real time-PCR. Results: BL21 was confirmed with an 1152 bp band on the agarose gel. A 39 kDa expression band on the SDS gel confirmed the gene expression. Performing 20 RSM-designed experiments, the optimum levels for IPTG concentration and OD were determined as 0.34mM and 5.6, respectively. Moreover, the optimum level of expression time was demonstrated to be 11.91 hours. The accuracy of the regression model for reteplase overexpression was confirmed by an F-value equal to 25.31 and a meager probability value [(Prob > F) < 0.0001]. The real-time-PCR results indicated that the performed calculations were highly accurate. Conclusion: The obtained results indicate that IPTG concentration, OD, and expression time are significantly involved in the augmentation of recombinant reteplase expression. To the best of our knowledge, this is the first study to assess the combined effect of these factors on reteplase expression. Further RSM-based experiments would bring about new insights regarding the best conditions for reteplase expression.

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