1 7 , 1 3 ; 2 24 w w w . r e a n i m a t o l o g y . c o mЦель исследования: изучить влияние инфузии этилетилгидроксипиридинасукцината (ЭМГПС) на ди намику паттернов мозгового кровотока у пострадавших в остром периоде тяжелой сочетанной черепно моз говой травмы.Материалы и методы исследования. Обследовали 2 группы больных по 25 человек в каждой с тяжелой сочетанной ЧМТ. Средний возраст составил 41,5 (29; 51) лет. Больным в 1 й группе (контрольной) прово дили стандартную интенсивную терапию, а во 2 й группе (исследуемой) дополнительно к стандартному ле чению проводили инфузию ЭМГПС в дозе 100 мг/час через инфузомат на протяжении 10 суток. Методи кой транскраниальной допплерографии (ТДГ) изучали показатели церебральной макроциркуляции (ПЦМ): систолическую скорость кровотока (V max ), диастолическую скорость кровотока (V min ), пульсацион ный индекс (PI) и индекс сопротивления (RI).Результаты исследования. В обеих группах наиболее частым видом нарушения мозгового кровотока (МК) при первичном исследовании был паттерн затрудненной перфузии: 15 и 16 случаев в 1 й и 2 й груп пах, соответственно. В 1 й группе в 4, а во 2 й в 3 случаях отмечали наличие мягкого ангиоспазма, а в 2 слу чаях в каждой группе отмечали признаки грубого ангиоспазма. У 2 больных в каждой группе отмечали пат терны гипоперфузии и гиперперфузии. У пациентов в 1 й группе на 3 е сутки исследования нормализация ПЦМ наблюдалась в 6, на 5 е сутки -в 8, на 7 е сутки -в 12, на 10 сутки -в 18 случаев, в то время, как у пациентов во 2 й группе на 3 е сутки нормализация ПЦМ наблюдалась в 12, на 5 е сутки -в 15, на 7 е сут ки -в 16, на 10 е сутки -в 20 случаях.Заключение. Чаще всего при первичном обследовании выявлялись паттерны затрудненной перфузии и ангиоспазма, которые трансформировались в паттерн нормоперфузии через стадию гиперперфузии (реак тивной гиперемии). Инфузия ЭМГПС в дозе 100 мг в час способствует нормализации параметров ПЦМ уже к 3-5 суткам. Ключевые слова: черепно мозговая травма; церебральная макроциркуляция; паттерны мозгового крово тока; этилметилгидроксипиридина сукцинатThe purpose of the investigation was to study the effect of the ethylmethylhydroxypyridine succinate (EMHPS) infusion on the dynamics of cerebral blood flow patterns in patients during the acute phase of severe concomitant traumatic brain injury.Materials and methods. The study involved two groups of patients, each of 25 persons aged 41.5 (29; 51) years on average, with a severe concomitant traumatic brain injury. The patients of the 1 st (control) group were cured with a standard intensive care while in the 2 nd (study) group the EMHPS infusion was added to the said standard treatment in a dose of 100 mg per hour through an infusion pump within 10 days. By transcranial dopplerography (TDG) testing the following cerebral macrocirculation parameters (CMP) were studied: systolic blood flow veloc ity (V max ), diastolic blood flow velocity (V min ), pulsation index (PI) and resistance index (RI). Влияние этилметилгидроксипиридина сукцината ВведениеИзучение механизмов защиты ...

Purpose: High-risk neuroblastoma is characterized by poor survival rates, and the development of improved therapeutic approaches is a priority. Temozolomide and topotecan show promising clinical activity against neuroblastoma. Poly(ADP-ribose) polymerase-1 (PARP-1) promotes DNA repair and cell survival following genotoxic insult; we postulated that its inhibition may enhance the efficacy of these DNA-damaging drugs in pediatric cancers. Experimental Design: We evaluated the chemosensitizing properties of the PARP inhibitor AG014699 (Pfizer, Inc.) in combination with temozolomide and topotecan, against human neuroblastoma cells and xenografts, alongside associated pharmacologic and toxicologic indices. Results: Addition of PARP-inhibitory concentrations of AG014699 significantly potentiated growth inhibition by both topotecan (1.5-to 2.3-fold) and temozolomide (3-to 10-fold) in vitro, with equivalent effects confirmed in clonogenic assays. In two independent in vivo models (NB1691 and SHSY5Y xenografts), temozolomide caused a xenograft growth delay, which was enhanced by co-administration of AG014699, and resulted in complete and sustained tumor regression in the majority (6 of 10; 60%) of cases. Evidence of enhanced growth delay by topotecan/AG014699 co-administration was observed in NB1691 xenografts. AG014699 metabolites distributed rapidly into the plasma (C max , 1.2-1.9 nmol/L at 30 min) and accumulated in xenograft tissues (C max ,1-2 Amol/L at 120 min), associated with a sustained suppression of PARP-1enzyme activity. Doses of AG014699 required for potentiation were not toxic per se. Conclusions: These data show enhancement of temozolomide and topotecan efficacy by PARP inhibition in neuroblastoma. Coupled with the acceptable pharmacokinetic, pharmacodynamic, and toxicity profiles of AG014699, our findings provide strong rationale for investigation of PARP inhibitors in pediatric early clinical studies.

Infusion of nerve growth factor (NGF) has been shown to be neuroprotective following traumatic brain injury (TBI). In this study, we tested the hypothesis that NGF-expressing human NT2N neurons transplanted into the basal forebrain of brain-injured mice can attenuate long-term cognitive dysfunction associated with TBI. Undifferentiated NT2 cells were transduced in vitro with a lentiviral vector to release NGF, differentiated into NT2N neurons by exposure to retinoic acid and transplanted into the medial septum of mice 24 h following controlled cortical impact (CCI) brain injury or sham injury. Adult mice (n = 78) were randomly assigned to one of four groups: (1) sham-injured and vehicle (serum-free medium)-treated, (2) brain-injured and vehicle-treated, (3) brain-injured engrafted with untransduced NT2N neurons, and (4) brain-injured engrafted with transduced NGF-NT2N neurons. All groups were immunosuppressed daily with cyclosporin A (CsA) for 4 weeks. At 1 month post-transplantation, animals engrafted with NGF-expressing NT2N neurons showed significantly improved learning ability (evaluated with the Morris water maze) compared to brain-injured mice receiving either vehicle (p < 0.05) or untransduced NT2N neurons (p < 0.01). No effect of NGF-secreting NT2N cells on motor function deficits at 1-4 weeks post-transplantation was observed. These data suggest that NGF gene therapy using transduced NT2N neurons (as a source of delivery) may selectively improve cognitive function following TBI.

Background:Temozolomide shows activity against medulloblastoma, the most common malignant paediatric brain tumour. Poly(ADP-ribose) polymerase (PARP) inhibitors enhance temozolomide activity in extracranial adult and paediatric human malignancies.Methods:We assessed the effect of AG-014699, a clinically active PARP inhibitor, on temozolomide-induced growth inhibition in human medulloblastoma models. Pharmacokinetic, pharmacodynamic and toxicity assays were performed in tumour-bearing mice.Results:Sensitivity to temozolomide in vitro was consistent with methylguanine methyltransferase (MGMT) and DNA mismatch repair (MMR) status; MGMT+ MMR+ D384Med cells (temozolomide GI50=220 μ), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMT− MMR+ D425Med cells were hypersensitive (GI50=9 μ) and not sensitised by AG-014699, whereas MGMT+ MMR− temozolomide-resistant D283Med cells (GI50=807 μ) were sensitised 20-fold. In xenograft models, co-administration of AG-014699 produced an increase in temozolomide-induced tumour growth delay in D384Med xenografts. Consistent with the in vitro data, temozolomide caused complete tumour regressions of D425Med xenografts, whereas D283Med xenografts were relatively resistant. AG-014699 was not toxic, accumulated and reduced PARP activity ⩾75% in xenograft and brain tissues.Conclusion:We show for the first time central nervous system penetration and inhibition of brain PARP activity by AG-014699. Taken together with our in vitro chemosensitisation and toxicity data, these findings support further evaluation of the clinical potential of AG-014699–temozolomide combinations in intra-cranial malignancies.

Baicalein (5,6,7-trihydroxyflavone, 1) is of interest because of its broad spectrum of biological activity. It is a constituent of the east Asian herbal remedy, "Sho-saiko-to". The 3D structure of 1 was determined using X-ray diffraction. The compound exists in an almost planar conformation with a C-2-C-1' bond distance of 1.476(5) A. Hydrogen-bonding interactions predominate in the crystal structure. The position of the three hydroxyl groups maximizes intramolecular hydrogen bonding, and each of the hydroxyl hydrogen atoms is a donor in a three-center hydrogen bond. The carbonyl oxygen, O-4, is an acceptor in an intramolecular hydrogen bond (with OH-5). Two molecules of 1 exist as hydrogen-bonded dimers related by inversion center (-x + 1, -y, -z + 1). O-4 is also an acceptor in an intermolecular hydrogen bond with OH-6. The planarity of the flavone framework is dependent on structural and/or electronic forces that stabilize the negative charge on the exocyclic oxygen atom, O-4. Compound 1, therefore, is planar in any situation where forces can stabilize the negative charge on O-4. Consistent with this, UV absorbance studies performed on 1-DNA complexes with varying concentrations of 1 strongly suggest intercalation of 1 within the double helix, followed by possible interstrand cross-links.