Magnetic resonance thermometry: methodology, pitfalls and practical solutions

Clinically established thermal therapies such as thermoablative approaches or adjuvant hyperthermia treatment rely on accurate thermal dose information for the evaluation and adaptation of the thermal therapy. Intratumoural temperature measurements have been correlated successfully with clinical end points. Magnetic resonance imaging is the most suitable technique for non-invasive thermometry avoiding complications related to invasive temperature measurements. Since the advent of MR thermometry two decades ago, numerous MR thermometry techniques have been developed, continuously increasing accuracy and robustness for in vivo applications. While this progress was primarily focused on relative temperature mapping, current and future efforts will likely close the gap towards quantitative temperature readings. These efforts are essential to benchmark thermal therapy efficiency, to understand temperature-related biophysical and physiological processes and to use these insights to set new landmarks for diagnostic and therapeutic applications. With that in mind, this review summarises and discusses advances in MR thermometry, providing practical considerations, pitfalls and technical obstacles constraining temperature measurement accuracy, spatial and temporal resolution in vivo. Established approaches and current trends in thermal therapy hardware are surveyed with respect to potential benefits for MR thermometry

Thermal magnetic resonance: physics considerations and electromagnetic field simulations up to 23.5 Tesla (1GHz)

Background: Glioblastoma multiforme is the most common and most aggressive malign brain tumor. The 5-year survival rate after tumor resection and adjuvant chemoradiation is only 10 %, with almost all recurrences occurring in the initially treated site. Attempts to improve local control using a higher radiation dose were not successful so that alternative additive treatments are urgently needed. Given the strong rationale for hyperthermia as part of a multimodal treatment for patients with glioblastoma, non-invasive radio frequency (RF) hyperthermia might significantly improve treatment results. Methods: A non-invasive applicator was constructed utilizing the magnetic resonance (MR) spin excitation frequency for controlled RF hyperthermia and MR imaging in an integrated system, which we refer to as thermal MR. Applicator designs at RF frequencies 300 MHz, 500 MHz and 1GHz were investigated and examined for absolute applicable thermal dose and temperature hotspot size. Electromagnetic field (EMF) and temperature simulations were performed in human voxel models. RF heating experiments were conducted at 300 MHz and 500 MHz to characterize the applicator performance and validate the simulations. Results: The feasibility of thermal MR was demonstrated at 7.0 T. The temperature could be increased by ~11 °C in 3 min in the center of a head sized phantom. Modification of the RF phases allowed steering of a temperature hotspot to a deliberately selected location. RF heating was monitored using the integrated system for MR thermometry and high spatial resolution MRI. EMF and thermal simulations demonstrated that local RF hyperthermia using the integrated system is feasible to reach a maximum temperature in the center of the human brain of 46.8 °C after 3 min of RF heating while surface temperatures stayed below 41 °C. Using higher RF frequencies reduces the size of the temperature hotspot significantly. Conclusion: The opportunities and capabilities of thermal magnetic resonance for RF hyperthermia interventions of intracranial lesions are intriguing. Employing such systems as an alternative additive treatment for glioblastoma multiforme might be able to improve local control by "fighting fire with fire". Interventions are not limited to the human brain and might include temperature driven targeted drug and MR contrast agent delivery and help to understand temperature dependent bio- and physiological processes in-vivo

Оценка биоэквивалентности двух таблетированных форм лизиноприла на здоровых добровольцах

Under cross, single, open, randomized trial with 1 week washout period, with two sequences of 18 volunteers studied bioequivalence coated tablets, two manufacturers of lisinopril (20 mg dose). The concentration of lisinopril in the plasma samples was determined using HPLC with fluorimetric detection within 72 hours for the investigated preparations the following pharmacokinetic parameters were calculated:AUC0-∞, Cmax, tmax, Cmax/AUC. 90% confidence interval relations AUC0-∞ compared drugs totaled 0.8520 — 1.2102 for Cmax — 0,9288 — 1,1451. In addition to the 90% confidence intervals, analysis of variance revealed no statistically significant differences between the studied drugs. Concluded bioequivalence compared drugs lisinopril.В рамках перекрёстного, однократного, открытого, рандомизированного исследования с периодом отмывки 1 неделя, с двумя последовательностями на 18 добровольцах изучена биоэквивалентность таблеток, покрытых оболочкой, лизиноприла двух производителей (доза 20 мг). Концентрацию лизиноприла в образцах плазмы крови определяли методом ВЭЖХ с флуориметрическим детектированием в течение 72 ч. Для исследуемых препаратов рассчитаны следующие фармакокинетические параметры: AUC0-∞, Cmax, tmax, Cmax/AUC. 90% доверительный интервал отношений AUC0-» сравниваемых препаратов составил 0,8520 — 1,2102 и для Cmax — 0,9288 — 1,1451. В дополнение к 90% доверительным интервалам, дисперсионный анализ не выявил статистически значимых различий между изучаемыми препаратами. Сделан вывод о биоэквивалентности сравниваемых препаратов лизиноприла

Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas

Local recurrence of glioblastomas is a major cause of patient mortality after definitive treatment. This review discusses the roles of the chemokine stromal cell-derived factor-1 and its receptor CXC chemokine receptor 4 (CXCR4) in affecting the sensitivity of glioblastomas to irradiation. Blocking these molecules prevents or delays tumour recurrence after irradiation by inhibiting the recruitment of CD11b+ monocytes/macrophages that participate in revascularising the tumour. We review the literature pertaining to the mechanism by which revascularisation occurs following tumour irradiation using experimental models. Areas of interest and debate in the literature include the process by which endothelial cells die after irradiation and the identity/origin of the cells that reconstitute the tumour blood vessels after injury. Understanding the processes that mediate tumour revascularisation will guide the improvement of clinical strategies for preventing recurrence of glioblastoma after irradiation

Исследование сравнительной биоэквивалентности препаратов Пиоглитазон таблетки, 20 мг (АО «Химфарм», Республика Казахстан) и Актос® таблетки, 30 мг («Eli Lilly Holdings, Takeda Global Research and Development Centre Europe Ltd»)

Within the cross, a single, open, randomized study with a two-week washout period, the two sequences has been studied bioequivalence of tablet forms two pioglitazone 18 volunteers (30 mg dosage). Plasma samples were analyzed by a validated HPLC-MS/MS within 48 hours. Analyzed for drugs following pharmacokinetic parameters were calculated: AUC0-t, Cmax, tmax, Cmax /AUC. 90% confidence interval for log-transformed values of AUC0-t was 0.945 — 1.066 and Cmax — 0,871 — 1,044. The study concluded that bioequivalence compared pioglitazone drugs.В рамках перекрёстного, однократного, открытого, рандомизированного исследования с двухнедельным периодом отмывки, с двумя последовательностями была изучена биоэквивалентность двух таблетированных форм пиог-литазона на 18 добровольцах (дозировка 30 мг). Образцы плазмы крови анализировали валидированным методом ВЭЖХ-МС/МС в течение 48 часов. Для анализируемых препаратов рассчитаны следующие фармакокинетические параметры: AUC0-t, Cmax, tmax, Cmax/AUC. 90% доверительный интервал для логарифмически преобразованных значений AUC0-t составил 0,945 — 1,066 и для Cmax — 0,871 — 1,044. По результатам исследования был сделан вывод о биоэквивалентности сравниваемых препаратов пиоглитазона

Исследование сравнительной фармакокинетики и биоэквивалентности препаратов Кардиоприл таблетки, 20 мг (АО «Химфарм», Республика Казахстан) и Моноприл® таблетки, 20 мг («Бристол-Майерс Сквибб С.Р.Л.», Италия)

In a single-dose, two-treatment, two-period, two-sequence crossover study with a 1-week washout period was carry out the bioequivalence study of two tablet coated formulation of fosinopril that given to 18 volunteers in equal doses (20 mg). Drug blood plasma concentrations were determined by validated LC-MS method for 48 hours. There were calculated the followed parameters: AUC 0-t ,Cmax, tmax , Cmax /AUC. 90% confidence interval for log-transformed AUC 0-tvalues was 0,9393 - 1,1473 and one for log-transformed Cmax was 0,8861 - 1,066, respectively. It was made the conclusion about bioequivalence of compared fosinopril formulations.В рамках перекрёстного, однократного, открытого, рандомизированного исследования с однонедельным периодом отмывки, с двумя последовательностями была изучена биоэквивалентность двух таблетированных форм фозиноприла на 18 добровольцах (дозировка 20 мг). Образцы плазмы крови анализировали валидированным методом ВЭЖХ-МС/МС в течение 48 часов. Для анализируемых препаратов рассчитаны следующие фармакокинетические параметры: AUC0-t, Cmax, tmax, Cmax/AUC. 90% доверительный интервал для логарифмически преобразованных значений AUC0-t составил 0,9393 - 1,1473 и для Cmax - 0,8861 - 1,066. По результатам исследования был сделан вывод о биоэквивалентности сравниваемых препаратов фозиноприла

Биоэквивалентность бисопролола, таблетки покрытые оболочкой 10 мг АО «Химфарм», Республики Казахстан

Within the cross, a single, open, randomized study with 10 day washout period, the two sequences has been studied bioequivalence of tablet forms two bisoprolol 18 volunteers (10 mg dosage). Plasma samples were analyzed by a validated HPLC-MS/MS within 48 hours. For preparations analyzed following pharmacokinetic parameters were calculated: AUC0-t, Cmax, Tmax , Cmax /AUC. 90% confidence interval for log-transformed values for AUC0-t was 0.9142—1.0568 for Cmax —0,9371 —1,0473. The study concluded that comparable drugs were bioequivalence of bisoprolol.В рамках перекрёстного, однократного, открытого, рандомизированного исследования с 10 дневным периодом отмывки, с двумя последовательностями была изучена биоэквивалентность двух таблетированных форм бисопролола на 18 добровольцах (дозировка 10 мг). Образцы плазмы крови анализировали валидированным методом ВЭЖХ-МС/МС в течение 48 часов. Для анализируемых препаратов рассчитаны следующие фармакокинетические параметры: AUC0-t, Cmax, tmax, Cmax/AUC. 90% доверительный интервал для логарифмически преобразованных значений для AUC0-t составил 0,9142 — 1,0568 и для Cmax — 0,9371 — 1,0473. По результатам исследования был сделан вывод о биоэквивалентности сравниваемого препарата бисопролола

Исследования биоэквивалентности Нипезама ретард таблетки, 400 мг (АО «Химфарм», Республика Казахстан) и Финлепсина® 400 ретард таблетки, 400 мг («Плива Краков, Фармацевтическая компания С.А.», Польша)

In a single-dose, two-treatment, two-period, two-sequence crossover study with a 1-month washout period was carry out the bioequivalence study of two tablet coated formulation of carbamazepine that given to 18 volunteers in equal doses (400 mg). Drug blood plasma concentrations were determined by validated LC-UV method for 120 hours. There were calculated the followed parameters: AUC0-t, Cmax , Tmax, Cmax /AUC. 90% confidence interval for log-transformed AUC. values was 0,93693 - 1,10204 and one for log-transformed Cmax was 0,91045 - 1,12287, respectively. It was made the conclusion about bioequivalence of compared carbamazepine formulations.В рамках перекрёстного, однократного, открытого, рандомизированного исследования с одномесячным периодом отмывки, с двумя последовательностями была изучена биоэквивалентность двух таблетированных форм карбамазепина на 18 добровольцах (дозировка 400 мг). Образцы плазмы крови анализировали валидированным методом ВЭЖХ-УФ в течение 120 часов. Для анализируемых препаратов рассчитаны следующие фармакокинетические параметры: AUC0-t, Cmax, Tmax, Cmax/AUC. 90% доверительный интервал для логарифмически преобразованных значений AUC0-t составил 0,93693 - 1,10204 и для Cmax - 0,91045 - 1,12287. По результатам исследования был сделан вывод о биоэквивалентности сравниваемых препаратов карбамазепина