Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16,

Proproten in Alleviating the Anticipatory Anxiety: Results of Experimental Study

Proceedings of the 9th International Multidisciplinary Conference «Stress and Behavior» Saint-Petersburg, Russia, 16–19 May 2005.Proproten, ultra-low doses of antibodies to brain S-100 protein for oral use (orally disintegrating tablets), have been successfully marketed in Russia since 1999 as a treatment option for alcohol withdrawal. In the earlier experimental studies, proproten was shown to possess a unique psychotropic profile including anxiolytic, anti-depressant and neuroprotective properties. The anticipatory anxiety of pain related to a medical procedure is one of the main problems of public health. The anticipation of pain is perhaps the biggest deterrent to the acceptance of professional dental care. The anticipation of pain phenomenon has been documented by an impressive number of clinical and experimental studies. Recently, research interest has moved to the effects of pain anticipation and the possibility of preventing them. This presented research was aimed at studying the influence of proproten on conditioned anxiety in the «anticipation of pain» test.Methods. Adult white outbread male rats (200–220 g) were exposed to an uncontrollable stressful condition (10 inescapable electric foot shocks, 0.45 mA, duration of 1 s in a 2 s interval) in a stainless steel grid floor chamber («Lafayette Instrument Co», USA). After the procedure the animals were taken out of the chamber and left in a cage given free access to water and food. The next day, in a 24-hour period, the rats were again placed in the chamber where they had experienced earlier foot shock for 5 min; although the painful stimuli were not delivered, the rats were stressed. The conditioned emotional response without and under provocation (a pencil was pointed to the rat’s head) was assessed during 4 min. The rats received 2.5 ml/kg of proproten i.g. (n = 20) or vehicle (n = 20) 30 min before they were placed in the chamber for the second time. Diazepam (1 mg/kg) was used as a reference drug.Results and discussions. The rats placed in the chamber where the electric shock had been delivered earlier showed a strong response to stress. The freezing reaction was found in 45 % of rats (55 % — under provocation), 35 % of animals were active (40 % — under provocation), while only 20 % of rats showed exploratory behavior (5 % — under provocation). The incidence of defecation, urination, and tachypnoe under the stressful conditions was rather high (Table 1). Proproten as well as diazepam greatly reduced the number of stress-induced events. Under stressful conditions, the proproten-treated animals were active 3 times as often as the diazepam-treated ones (4 times — under provocation). Notably, the anti-stress effect of proproten was more pronounced when the stress of anticipation of pain was aggravated by additional provocation. The incidence of freezing was 3 times lower in the group given proproten compared with diazepam (Table 1).Conclusions. In the «anticipation of pain» test, the anti-stress activity of proproten was equal to that of diazepam. Proproten exerted influence on both the rats with active, aggressive behavior and on the animals freezing in the response to the stress, while diazepam mostly modified the active stress-related behavior. In conclusion, proproten was shown to meet the medical needs of the patients who are about to undergo medical procedures and show anticipatory anxiety. Randomized clinical trials are to be conducted to confirm the above-mentioned activity in clinical practice

Первые данные о результатах международного многоцентрового клинического исследования RheoSTAT-CP0691 по эффективности и безопасности инфузионного раствора Реосорбилакт® в комплексной терапии гнойного перитонита

Generalized forms of peritonitis are a major factor leading to non-traumatic mortality in all cases of emergency care and the second leading cause of sepsis in critically ill patients. Objective of this study was to evaluate the efficacy and safety of multicomponent infusion solution Reosorbilact in the treatment of patients diagnosed with purulent peritonitis. An international multicenter randomized study included 181 patients aged from 18 to 60 years with a diagnosis of purulent peritonitis. Patients received therapy with Reosorbilact according to the prescribing information for use. The primary endpoint of the effectiveness was change in SOFA scale on day 3 of therapy. Changes in APACHE II, SAPS II, MODS, and MPI scores as well as changes in endogenous intoxication markers on day 3 of therapy were considered as secondary endpoints. Safety was assessed by analysis of adverse events (AE) and vital signs after 3 days of therapy. On day 3 of treatment with Reosorbilact statistically significant changes were observed in SOFA (1.80 ± 0.91 points), MODS (1.45 ± 0.76 points) and MPI (1.84 ± 5.03 points) scales. There was a statistically significant improvement in markers of endogenous intoxication (creatinine, bilirubin, white blood cell count, C-reactive protein, neutrophil to lymphocyte ratio) on day 3 of treatment. The majority of AE (98.99 %) were mild. No AE were associated with the study preparation and did not result in the patient’s withdrawal from the study. According to the results of RheoSTAT-CP0691, Rheosorbilact is an effective and safe drug for the treatment of patients with purulent peritonitis. It is advisable to include Rheosorbilact in routine treatment algorithms for patients with purulent peritonitis.Генералізовані форми перитоніту є основним фактором, який призводить до смерті, що не спричинена травмами, в усіх випадках надання невідкладної допомоги, та другою провідною причиною розвитку сепсису у тяжкохворих пацієнтів. Метою цього дослідження було оцінити ефективність і безпеку багатокомпонентного інфузійного розчину Реосорбілакт у терапії пацієнтів з діагнозом гнійного перитоніту. У міжнародному багатоцентровому рандомізованому дослідженні взяв участь 181 пацієнт віком від 18 до 60 років із діагнозом “гнійний перитоніт”. Пацієнти отримували терапію препаратом Реосорбілакт у дозуванні відповідно до інструкції застосування. Первинним показником ефективності терапії розглядалася зміна оцінки за шкалою SOFA на 3-й день терапії. Як вторинні показники розгля- далися зміни оцінки за шкалами APACHE II, SAPS II, MODS і MPI, а також зміна маркерів ендогенної інтоксикації на 3-й день терапії. Безпека препарату оцінювалася за допомогою аналізу небажаних явищ (НЯ) та життєво важливих показників через 3 дні терапії. На 3-й день лікування інфузійним розчином Реосорбілакт було зафіксовано статистично значущі зміни оцінки за шкалами SOFA (на 1,80 ± 0,91 бала), MODS (на 1,45 ± 0,76 бала) та MPI (на 1,84 ± 5,03 бала). Крім того, було виявлено статистично значуще покращення маркерів ендогенної інтоксикації (концентрації креатиніну, білірубіну, кількість лейкоцитів, рівень С-реактивного білка, співвідношення нейтрофілів і лімфоцитів) на 3-й день лікування. Більшість НЯ (98,99 %) були легкими. Жодне з НЯ не було пов’язане з досліджуваним препаратом і не призве- ло до вибування пацієнта з дослідження. Згідно з отриманими результатами, Реосорбілакт є ефективним і безпечним препаратом для лікування пацієнтів з гнійним перитонітом. Дослідження RheoSTAT-CP0691 обґрунтовує доцільність включення препарату Реосорбілакт® у рутинні алгоритми лікування пацієнтів з гнійним перитонітом.Генерализованные формы перитонита являются основным фактором смерти, не вызванной травмами, во всех случаях оказания неотложной помощи, и второй ведущей причиной развития сепсиса у тяжелобольных пациентов. Целью данного исследования было оценить эффективность и безопасность многокомпонентного инфузионного раствора Реосорбилакт в терапии пациентов с диагнозом гнойного перитонита. В международном многоцентровом рандомизиро- ванном исследовании принял участие 181 пациент в возрасте от 18 до 60 лет с диагнозом “гнойный перитонит”. Пациенты получали терапию препаратом Реосорбилакт в дозировке согласно инструкции по применению препарата. Первичным показателем эффективности терапии рассматривалось изменение оценки по шкале SOFA на 3-й день терапии. В качестве вторичных показателей рассматривались изменения оценки по шкалам APACHE II, SAPS II, MODS и MPI, а также изменение маркеров эндогенной интоксикации на 3-й день терапии. Безопасность препарата оценивалась с помощью анализа нежелательных явлений (НЯ) и жизненно важных показателей через 3 дня терапии. На 3-й день лечения Реосорбилактом были зафиксированы статистически значимые изменения оценки по шкалам SOFA (на 1,80 ± 0,91 балла), MODS (на 1,45 ± 0,76 балла) и MPI (на 1,84 ± 5,03 балла). Кроме того, было выявлено статистически значимое улучшение маркеров эндогенной интоксикации (концентрации креатинина, билирубина, количество лейкоцитов, уровень С-реактивного белка, соотноше- ние нейтрофилов и лимфоцитов) на 3-й день лечения. Большинство НЯ (98,99 %) были легкими. Ни одно из НЯ не было связано с препаратом исследования и не привело к выбыванию пациента из исследования. Согласно полученным результатам RheoSTAT-CP0691, Реосорбилакт является эффективным и безопасным препаратом для лечения пациентов с гнойным перитонитом. Целесообразным является включение препарата Реосорбилакт в рутинные алгоритмы лечения пациентов с гнойным перитонитом

Proproten in Alleviating the Anticipatory Anxiety: Results of Experimental Study

Proceedings of the 9th International Multidisciplinary Conference «Stress and Behavior» Saint-Petersburg, Russia, 16–19 May 2005.Proproten, ultra-low doses of antibodies to brain S-100 protein for oral use (orally disintegrating tablets), have been successfully marketed in Russia since 1999 as a treatment option for alcohol withdrawal. In the earlier experimental studies, proproten was shown to possess a unique psychotropic profile including anxiolytic, anti-depressant and neuroprotective properties. The anticipatory anxiety of pain related to a medical procedure is one of the main problems of public health. The anticipation of pain is perhaps the biggest deterrent to the acceptance of professional dental care. The anticipation of pain phenomenon has been documented by an impressive number of clinical and experimental studies. Recently, research interest has moved to the effects of pain anticipation and the possibility of preventing them. This presented research was aimed at studying the influence of proproten on conditioned anxiety in the «anticipation of pain» test.Methods. Adult white outbread male rats (200–220 g) were exposed to an uncontrollable stressful condition (10 inescapable electric foot shocks, 0.45 mA, duration of 1 s in a 2 s interval) in a stainless steel grid floor chamber («Lafayette Instrument Co», USA). After the procedure the animals were taken out of the chamber and left in a cage given free access to water and food. The next day, in a 24-hour period, the rats were again placed in the chamber where they had experienced earlier foot shock for 5 min; although the painful stimuli were not delivered, the rats were stressed. The conditioned emotional response without and under provocation (a pencil was pointed to the rat’s head) was assessed during 4 min. The rats received 2.5 ml/kg of proproten i.g. (n = 20) or vehicle (n = 20) 30 min before they were placed in the chamber for the second time. Diazepam (1 mg/kg) was used as a reference drug.Results and discussions. The rats placed in the chamber where the electric shock had been delivered earlier showed a strong response to stress. The freezing reaction was found in 45 % of rats (55 % — under provocation), 35 % of animals were active (40 % — under provocation), while only 20 % of rats showed exploratory behavior (5 % — under provocation). The incidence of defecation, urination, and tachypnoe under the stressful conditions was rather high (Table 1). Proproten as well as diazepam greatly reduced the number of stress-induced events. Under stressful conditions, the proproten-treated animals were active 3 times as often as the diazepam-treated ones (4 times — under provocation). Notably, the anti-stress effect of proproten was more pronounced when the stress of anticipation of pain was aggravated by additional provocation. The incidence of freezing was 3 times lower in the group given proproten compared with diazepam (Table 1).Conclusions. In the «anticipation of pain» test, the anti-stress activity of proproten was equal to that of diazepam. Proproten exerted influence on both the rats with active, aggressive behavior and on the animals freezing in the response to the stress, while diazepam mostly modified the active stress-related behavior. In conclusion, proproten was shown to meet the medical needs of the patients who are about to undergo medical procedures and show anticipatory anxiety. Randomized clinical trials are to be conducted to confirm the above-mentioned activity in clinical practice

Investigation of an outbreak of bloody diarrhea complicated with hemolytic uremic syndrome

In July–August 2009, eight patients with bloody diarrhea complicated by hemolytic uremic syndrome (HUS) were admitted to hospitals in Tbilisi, Georgia. We started active surveillance in two regions for bloody diarrhea and post-diarrheal HUS. Of 25 case-patients who developed HUS, including the initial 8 cases, half were ⩾15 years old, 67% were female and seven (28%) died. No common exposures were identified. Among 20 HUS case-patients tested, Shiga toxin was detected in the stools of 2 patients (one with elevated serum IgG titers to several Escherichia coli serogroups, including O111 and O104). Among 56 persons with only bloody diarrhea, we isolated Shiga toxin-producing E. coli (STEC) O104:H4 from 2 and Shigella from 10; 2 had serologic evidence of E. coli O26 infection. These cases may indicate a previously unrecognized burden of HUS in Georgia. We recommend national reporting of HUS and improving STEC detection capacity