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Неудача нафамостата
В клиническом испытании проверили как работает препарат нафамостат для лечения осложненного ковида (когда есть пневмония). Опытной группе пациентов в рандомизированном контролируемом трейле вводили преапарт внутривенно, а второй группе ( сходной по возрасту, полу, тяжести ковида (нужна кислородная поддержка и "матовое стекло") и хроническим болезням), контрольной, было предложено "обычное" в таких случаях симптоматическое лечение.
Выбор пал на нафамостат как препарат от ковида, тк он является антикоагулянтом, ингибитором сериновой протеазы (transmembrane protease serine 2 (TMPRSS2), и потенциально обладает противовирусным эфектом, включая от коронавируса САРС2. Во всяком случае " в пробирке" он показывал заметный эффект.
Увы, надежы на него не поправдались.
У группы больных, которая получала лечение препаратом (continuous infusion at a dose of 0.2 mg/kg/hr through a dedicated intravenous cannula), в течении 7 дней, некоторые покзатели были хуже, чем при "стандартном лечении".
Наблюдалось больше ковидных осложнений (78% вс 57% в контроле). Один пациент из опытной группы во время лечения получил легочную тромбоэмболию, другой ишемический инстульт. Опытная группа имела дольшее время пребывания в госпитале, и ей нужно было больше дней на кислороде (+2 дня).
Был выше уровень креатинина, Д-димера, очень высокие уровни калия в крови.. Воспалителные маркеры, иммуно-клеточные нарушения, уровни вируса были примерно одинаковые. Несмотря на продемонстрированные (по сравнению с контролем) антифибринолитические свойства, тромбоэласометрия не показала антикоагуляционного эффекта у пациентов при лечении ковида нафамостатом. Потому авторы склоняются к мысли, что препарат скорее сработал как про-тромботик (хотя уровни антитромбина и протеина С были выше у тех кто лечился нафамостатом).
Фармакокинетика показала что в крови ковидных больных препарат очень быстро деградирует на нерабочие компоненты.
И в опытной и в контрольной группе умерло от ковида в госпитале по 3 пациента.
Так что, согласно выводам исследователей- у госпитализивраонных с ковидным пневмонитов пациентов нафамостат не показал ни противовоспалительной, ни антивирусной (показатели вирусной нагурзки вобоих группах не отличались, одинаково снижаясь за веремя лечения в госпитале), ни антикоагулятной активности, и продемонстрировал побочки (гиперкалиемия).
Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups. Conclusion In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.
Nafamostat was delivered at its recommended dose for its licenced indication. Intravenous Nafamostat treatment compared to SoC produced more AEs without any evidence of beneficial effects. Intravenous Nafamostat had an unfavourable PK profile when used in patients with COVID-19. Compound screens have revealed that Nafamostat is one of the most potent inhibitors of SARS-CoV-2 viral entry into lung epithelial cells, with a greater than 600-fold potency over other antivirals [14]. As Nafamostat has anticoagulant and anti-inflammatory effects, the combination of these properties has led to intravenous Nafamostat being promoted as a promising therapeutic for COVID-19
Thus, to assess safety and PK of intravenous Nafamostat, we performed an incisive experimental medicine clinical trial in a small cohort of hospitalised patients with COVID-19 pneumonitis. In this cohort whilst there were no SAEs, there were a larger number of AEs within the intravenous Nafamostat treatment group and patients required oxygen for longer. The treatment course was discontinued early in 29% of patients indicating poor tolerability. We observed six cases of moderate hyperkalaemia in the intravenous Nafamostat arm, which prompted the end of treatment. Hyperkalaemia is a well described and widely reported side effect of intravenous Nafamostat owing to the effect of the metabolites on sodium conductance in the renal cortical collecting duct, thereby impairing urinary potassium excretion [18]. Notably, significantly higher creatinine levels were observed for patients randomised to intravenous Nafamostat compared to SoC.
Intravenous Nafamostat demonstrated a poor PK profile with undetectable levels in most patients with COVID-19 pneumonitis. Chemically, Nafamostat is an ester conjugate of p-guanidinobenzoic acid (GBA) and 6-amidino-2-naphthol. The ester site is described as the “reaction centre” as well as the site for the catabolic changes. Nafamostat has been reported to inhibit the activity of TMPRSS2 with an IC50 of between 5-55nM[7]. It is known that the plasma half-life (t1/2) of Nafamostat is short - between 23.1min and 1.84hr[19] and thus a continuous infusion is required to achieve a steady-state concentration sufficient to inhibit therapeutic targets. In this trial we used a dose of 0.2mg/kg/hr which is the current clinically licensed dose of Nafamostat for DIC and pancreatitis in Japan. The half-maximal inhibitory concentration (IC50) of Nafamostat in preventing infection of alveolar epithelial cells by SARS-CoV-2 is in the range of 5-10 nM[20]. The steady-state plasma concentrations of Nafamostat when infused to patients with DIC at 0.1 mg/kg/hr or 0.2 mg/kg/h is reported to be between 14-130 ng/mL, which exceeds the IC50 for TMPRSS2. PK analysis shows that with the exception of two patients, negligible levels of Nafamostat was circulating when administered by continuous intravenous infusion in COVID-19 patients. Detectable levels of the metabolite support a rapid breakdown in vivo.
A potential method to observe hypercoagulability in COVID-19 is TEM. It provides measurements of clot formation, clot strength and clot lysis by recording the elasticity of a blood clot from the formation of fibrin for a standardised period of time. Exploratory studies examining the use of TEM in COVID-19 have confirmed hypercoagulable profiles with derangement of fibrinogen and platelet function [28]. This was supported by the data we observed. In most patients receiving intravenous Nafamostat, little or no anticoagulant effect was evident, however an antifibrinolytic effect was observed. The antifibrinolytic effect could potentially have a procoagulant effect, though the size of the effect was small compared to that seen when an antifibrinolytic drug such as tranexamic acid is given
In summary, intravenous Nafamostat did not influence the rate of change in any immune or inflammatory parameters showing measurable alterations during the time on trial. In conclusion, treatment of patients hospitalised with COVID-19 using continuous intravenous Nafamostat was poorly tolerated, demonstrating more AEs than the SoC group
Выбор пал на нафамостат как препарат от ковида, тк он является антикоагулянтом, ингибитором сериновой протеазы (transmembrane protease serine 2 (TMPRSS2), и потенциально обладает противовирусным эфектом, включая от коронавируса САРС2. Во всяком случае " в пробирке" он показывал заметный эффект.
Увы, надежы на него не поправдались.
У группы больных, которая получала лечение препаратом (continuous infusion at a dose of 0.2 mg/kg/hr through a dedicated intravenous cannula), в течении 7 дней, некоторые покзатели были хуже, чем при "стандартном лечении".
Наблюдалось больше ковидных осложнений (78% вс 57% в контроле). Один пациент из опытной группы во время лечения получил легочную тромбоэмболию, другой ишемический инстульт. Опытная группа имела дольшее время пребывания в госпитале, и ей нужно было больше дней на кислороде (+2 дня).
Был выше уровень креатинина, Д-димера, очень высокие уровни калия в крови.. Воспалителные маркеры, иммуно-клеточные нарушения, уровни вируса были примерно одинаковые. Несмотря на продемонстрированные (по сравнению с контролем) антифибринолитические свойства, тромбоэласометрия не показала антикоагуляционного эффекта у пациентов при лечении ковида нафамостатом. Потому авторы склоняются к мысли, что препарат скорее сработал как про-тромботик (хотя уровни антитромбина и протеина С были выше у тех кто лечился нафамостатом).
Фармакокинетика показала что в крови ковидных больных препарат очень быстро деградирует на нерабочие компоненты.
И в опытной и в контрольной группе умерло от ковида в госпитале по 3 пациента.
Так что, согласно выводам исследователей- у госпитализивраонных с ковидным пневмонитов пациентов нафамостат не показал ни противовоспалительной, ни антивирусной (показатели вирусной нагурзки вобоих группах не отличались, одинаково снижаясь за веремя лечения в госпитале), ни антикоагулятной активности, и продемонстрировал побочки (гиперкалиемия).
Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. The Nafamostat group developed significantly higher plasma creatinine levels, more adverse events and a lower number of oxygen free days. There were no other statistically significant differences in the primary or secondary endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed an antifibrinolytic profile, and no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D Dimers compared to SoC. There were no differences in cytokine profile and immune cell phenotype and viral loads between the groups. Conclusion In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Given the number of negative trials with repurposed drugs, our experimental medicine trial highlights the value of PK/PD studies prior to selecting drugs for efficacy trials. Given the mechanism of action, further evaluation of Nafamostat delivered via a different route may be warranted. This trial demonstrates the importance of experimental trials in new disease entities such as COVID-19 prior to selecting drugs for larger trials.
Nafamostat was delivered at its recommended dose for its licenced indication. Intravenous Nafamostat treatment compared to SoC produced more AEs without any evidence of beneficial effects. Intravenous Nafamostat had an unfavourable PK profile when used in patients with COVID-19. Compound screens have revealed that Nafamostat is one of the most potent inhibitors of SARS-CoV-2 viral entry into lung epithelial cells, with a greater than 600-fold potency over other antivirals [14]. As Nafamostat has anticoagulant and anti-inflammatory effects, the combination of these properties has led to intravenous Nafamostat being promoted as a promising therapeutic for COVID-19
Thus, to assess safety and PK of intravenous Nafamostat, we performed an incisive experimental medicine clinical trial in a small cohort of hospitalised patients with COVID-19 pneumonitis. In this cohort whilst there were no SAEs, there were a larger number of AEs within the intravenous Nafamostat treatment group and patients required oxygen for longer. The treatment course was discontinued early in 29% of patients indicating poor tolerability. We observed six cases of moderate hyperkalaemia in the intravenous Nafamostat arm, which prompted the end of treatment. Hyperkalaemia is a well described and widely reported side effect of intravenous Nafamostat owing to the effect of the metabolites on sodium conductance in the renal cortical collecting duct, thereby impairing urinary potassium excretion [18]. Notably, significantly higher creatinine levels were observed for patients randomised to intravenous Nafamostat compared to SoC.
Intravenous Nafamostat demonstrated a poor PK profile with undetectable levels in most patients with COVID-19 pneumonitis. Chemically, Nafamostat is an ester conjugate of p-guanidinobenzoic acid (GBA) and 6-amidino-2-naphthol. The ester site is described as the “reaction centre” as well as the site for the catabolic changes. Nafamostat has been reported to inhibit the activity of TMPRSS2 with an IC50 of between 5-55nM[7]. It is known that the plasma half-life (t1/2) of Nafamostat is short - between 23.1min and 1.84hr[19] and thus a continuous infusion is required to achieve a steady-state concentration sufficient to inhibit therapeutic targets. In this trial we used a dose of 0.2mg/kg/hr which is the current clinically licensed dose of Nafamostat for DIC and pancreatitis in Japan. The half-maximal inhibitory concentration (IC50) of Nafamostat in preventing infection of alveolar epithelial cells by SARS-CoV-2 is in the range of 5-10 nM[20]. The steady-state plasma concentrations of Nafamostat when infused to patients with DIC at 0.1 mg/kg/hr or 0.2 mg/kg/h is reported to be between 14-130 ng/mL, which exceeds the IC50 for TMPRSS2. PK analysis shows that with the exception of two patients, negligible levels of Nafamostat was circulating when administered by continuous intravenous infusion in COVID-19 patients. Detectable levels of the metabolite support a rapid breakdown in vivo.
A potential method to observe hypercoagulability in COVID-19 is TEM. It provides measurements of clot formation, clot strength and clot lysis by recording the elasticity of a blood clot from the formation of fibrin for a standardised period of time. Exploratory studies examining the use of TEM in COVID-19 have confirmed hypercoagulable profiles with derangement of fibrinogen and platelet function [28]. This was supported by the data we observed. In most patients receiving intravenous Nafamostat, little or no anticoagulant effect was evident, however an antifibrinolytic effect was observed. The antifibrinolytic effect could potentially have a procoagulant effect, though the size of the effect was small compared to that seen when an antifibrinolytic drug such as tranexamic acid is given
In summary, intravenous Nafamostat did not influence the rate of change in any immune or inflammatory parameters showing measurable alterations during the time on trial. In conclusion, treatment of patients hospitalised with COVID-19 using continuous intravenous Nafamostat was poorly tolerated, demonstrating more AEs than the SoC group