Розробка спектрофотометричної методики кількісного визначення суми фенольних сполук у перерахунку на 6-гінгерол у таблетках на основі сухого екстракту імбиру лікарського

Zingiber officinale has a wide range of pharmacological properties, including hypoglycemic and antioxidant ones. Most literature sources associate the pharmacological activity and mechanism of action of ginger with the content of phenolic compounds, and in particular gingerol.Aim. To develop the spectrophotometric method for the quantitative determination of the total amount of phenolic compounds calculated with reference to 6-gingerol in tablets based on a dry ginger extract.Materials and methods. The study object were tablets with an average weight of 0.5 g containing 0.3 g of a dry ginger extract (manufacturer – “Medagroprom”, Dnipro) obtained by the direct compression method. The spectrophotometric method was used to determine phenolic compounds calculated with reference to 6-gingerol.Results and discussion. The spectral characteristics of a standard sample of 6-gingerol, a predominant substance among biologically active phenolic compounds of ginger, have been studied. It has been shown that its absorption spectrum in the range from 220 to 400 nm contains one absorption band with a maximum at 281 nm, which can be used as an analytical absorption band for the quantitative determination by absorption spectrophotometry. It has been proven that excipients do not interfere with the quantitative determination of the total amount of phenolic compounds in the composition of tablets with a dry extract of ginger since they do not absorb electromagnetic radiation in the region of the analytical maximum. It has been found that the content of the total amount of phenolic compounds calculated with reference to 6-gingerol in the experimental batch of tablets is 0.03556 ± 0.0088 g/tab. The relative uncertainty of the mean determination was 1.007 %.Conclusions. The spectrophotometric method for the quantitative determination of the total amount of phenolic compounds calculated with reference to 6-gingerol in tablets based on a dry ginger extract with the subsequent calculation by the standard method has been developed. It can be used to develop quality control procedures for the tablets under research.Имбирь лекарственный имеет широкий спектр фармакологических свойств, среди которых гипогликемические и антиоксидантные. Большинство литературных источников связывает фармакологическую активность и механизм действия имбиря с содержанием в нем фенольных соединений и в частности гингерола.Целью данной работы является разработка спектрофотометрической методики количественного определения суммы фенольных соединений в пересчете на 6-гингерол в таблетках на основе сухого экстракта имбирялекарственного.Материалы и методы. Объектом исследования были таблетки, полученные методом прямого прессования со средней массой 0,5 г, содержащие 0,3 г сухого экстракта имбиря лекарственного (производитель «Медагропром», г. Днепро). Для определения фенольных соединений в пересчете на 6-гингерол использовали спектрофотометрическую методику.Результаты и их обсуждение. Изучены спектральные характеристики стандартного образца 6-гингерола, который является преобладающим веществом среди биологически активных фенольных соединений имбирялекарственного. Показано, что в его абсорбционном спектре в области от 220 до 400 нм содержится одна полоса поглощения с максимумом при 281 нм, которая может быть использована как аналитическая полосапоглощения для количественного определения методом абсорбционной спектрофотометрии. Доказано, что вспомогательные вещества не мешают количественному определению суммы фенольных соединений в составе таблеток с сухим экстрактом имбиря, поскольку не поглощают электромагнитные излучения в области аналитического максимума. Установлено, что содержание суммы фенольных соединений в пересчете на 6-гингерол в экспериментальной серии таблеток составляет 0,03556 ± 0,0088 г/т. Относительная неопределенность среднего определения составила 1,007 %.Выводы. Разработана спектрофотометрическая методика количественного определения суммы фенольных соединений в пересчете на 6-гингерол в таблетках на основе сухого экстракта имбиря лекарственного с последующим расчетом по методу стандарта, которая может быть использована при разработке методик контроля качества исследуемых таблеток.Імбир лікарський має широкий спектр фармакологічних властивостей, серед яких гіпоглікемічні та антиоксидантні. Більшість літературних джерел пов’язує фармакологічну активність та механізм дії імбиру з вмістом у ньому фенольних сполук, зокрема гінгеролу.Метою даної роботи є розробка спектрофотометричної методики кількісного визначення суми фенольних сполук у перерахунку на 6-гінгерол у таблетках на основі сухого екстракту імбиру лікарського.Матеріали та методи. Об’єктом дослідження були таблетки, отримані методом прямого пресування з середньою масою 0,5 г, що містять 0,3 г сухого екстракту імбиру лікарського (виробник «Медагропром», м. Дніпро). Для визначення фенольних сполук у перерахунку на 6-гінгерол використовували спектрофотометричну методику.Результати та їх обговорення. Вивчені спектральні характеристики стандартного зразка 6-гінгеролу, який є переважаючою речовиною серед біологічно активних фенольних сполук імбиру лікарського. Показано, що у його абсорбційному спектрі в області від 220 до 400 нм міститься одна смуга поглинання з максимумом при 281 нм, яка може бути використана як аналітична смуга вбирання для кількісного визначення методом абсорбційної спектрофотометрії. Доведено, що допоміжні речовини не заважають кількісному визначенню суми фенольних сполук у складі таблеток з сухим екстрактом імбиру, оскільки не поглинають електромагнітного випромінювання в області аналітичного максимуму. Встановлено, що вміст суми фенольних сполук у перерахунку на 6-гінгерол в експериментальній серії таблеток складає 0,03556 ± 0,0088 г/т. Відносна невизначеність середнього визначення склала 1,007 %.Висновки. Розроблено спектрофотометричну методику кількісного визначення суми фенольних сполук у перерахунку на 6-гінгерол у таблетках на основі сухого екстракту імбиру лікарського з наступним розрахунком за методом стандарту, яка може бути використана при розробці методик контролю якості досліджуваних таблеток

Методичний підхід до визначення оптимального вмісту допоміжних речовин у складі таблеток

Aim. To determine the algorithm of the optimal amount of excipients in the composition of tablets based on common ginger. Materials and methods. The study object was the regression equations determining the quantitative effect of excipients in the composition of the dosage form on the target pharmacopeial characteristics. The mathematical processing of these equations was carried out using the Mathcad 15 computer program according to the algorithm proposed. Results and discussion. It has been proposed to use the approximation function to determine the level of optimization. The approximation function is the sum of the squares of deviations of the objective functions from their optimal values. It has been proven that identification of mathematical models in pharmaceutical studies with three dependent factors, which total value is determined by the quantitative composition of a dosage form and is fixed at a certain level, is difficult to perform due to the complicated interpretation of multiple regression parameters as characteristics of factors in an isolated form through their correlation. The region for the optimal solution has been proposed with respect to the values of factors and effective indicators of a multiple regression model. The methodological approach to determining the optimal content of excipients in the composition of the given dosage form has been proposed. Conclusions. The optimal content of excipients – neusilin and colidone – has been determined while developing the composition of tablets based on common ginger with the necessary pharmacological and technological indicators that meet the requirements of the State Pharmacopoeia of Ukraine. The approach to the formation of the region offeasibility in two-way studies has been considered. Using the theory of multi-vector optimization a criterion has been developed; it allows determining the optimal feasible solution in the region under conditions of restrictions both by factors and target indicators.Целью работы является определение алгоритма установления оптимального количества вспомогательных веществ в составе таблеток на основе имбиря лекарственного. Материалы и методы. Объектом исследований были уравнения регрессии, определяющие количественное влияние вспомогательных веществ в составе лекарственной формы на целевые фармакопейные характеристики. Математическую обработку указанных уравнений проводили с использованием компьютерной программы Mathcad 15 по предложенному алгоритму.Результаты и их обсуждение. Предложено для установления уровня оптимизации применять функцию приближения. Функция приближения является суммой квадратов отклонений целевых функций от своих оптимальных значений. Доказано, что проведение идентификации математических моделей в фармацевтическихисследованиях с тремя зависимыми факторами, суммарное значение которых определяется количественным составом лекарственной формы и фиксируется на определенном уровне, проводить трудно вследствие осложнения интерпретации параметров множественной регрессии как характеристик факторов в изолированном виде из-за их коррелируемости. Предложена область определения оптимального решения относительно значения факторов и результативных показателей множественной регрессионной модели. Предложен методический подход к установлению оптимального содержания вспомогательных веществ в составе указанной лекарственной формы. Выводы. Установлено оптимальное содержание вспомогательных веществ (неусилина и колидона) для разработки рецептуры таблеток на основе имбиря лекарственного с необходимыми фармакотехнологическими показателями, соответствующими требованиям Государственной фармакопеи Украины. Рассмотрен подход к формированию области допустимых решений в двухфакторных исследованиях. С использованием теории многовекторной оптимизации разработан критерий, позволяющий определить оптимальное решение с допустимой области в условиях ограничений как по факторам, так и по целевым показателям.Мета роботи – описати алгоритм визначення оптимальної кількості допоміжних речовин у складі таблеток на основі імбиру лікарського. Матеріали та методи. Об’єктом дослідження були рівняння регресії, що визначають кількісний вплив допоміжних речовин у складі лікарської форми на цільові фармакопейні характеристики. Математичне оброблення зазначених рівнянь виконували з використанням комп’ютерної програми Mathcad 15 за запропонованим алгоритмом. Результати та їх обговорення. Запропоновано для визначення рівня оптимізації застосовувати функцію наближення. Функція наближення є сумою квадратів відхилень цільових функцій від своїх оптимальних значень. Доведено, що проведення ідентифікації математичних моделей у фармацевтичних дослідженнях з трьома залежними факторами, сумарне значення яких визначається кількісним складом лікарської форми та фіксується на певному рівні, проводити важко внаслідок ускладнення інтерпретації параметрів множинної регресії як характеристик факторів у ізольованому вигляді через їх корельованість. Окреслено область визначення оптимального рішення стосовно значення факторів і результативних показників множинної регресійної моделі. Запропоновано методичний підхід до визначення оптимального вмісту допоміжних речовин у складі зазначеної лікарської форми. Висновки. Визначено оптимальний вміст допоміжних речовин (неусиліну та колідону) для розроблення рецептури таблеток на основі імбиру лікарського з необхідними фармакотехнологічними показниками, що відповідають вимогам Державної фармакопеї України. Розглянуто підхід до формування області допускних рішень у двофакторних дослідженнях. Із застосуванням теорії багатовекторної оптимізації розроблено критерій, що дозволяє визначити оптимальне рішення з допускної області в умовах обмежень як за факторами, так і за цільовими показниками

Experimental rationale of selection of the hypoglicemic dose of ginger dry extract on normoglycemic rats

Modern regimens for treatment of type 2 diabetes include various groups of oral hypoglycemic agents, most of which could cause side effects. Pharmacological activity of these medicines with long-term use is often reduced, which indicates the need to expand the range of new antidiabetic drugs. Promising antidiabetic agents are substances of plant origin that have a wide range of pharmacological effects, minimal adverse reactions and can be an effective preventive and curative adjunct to the pharmacotherapy of diabetes mellitus. Among medicinal plants with hypoglycemic action, ginger medicinal (Zingiber officinale) is promising for the development of a new antidiabetic agent. The aim of the work was a screening study of the hypoglycemic effect of the extract of ginger. The subject of the study was a dry of Ginger extract medicinal (Medagroprom, Dnipro), obtained from ginger rhizomas by extraction with 50% alcohol and spray-drying. The substance of Ginger extract is a fine-grained powder of light brown color with a peculiar scent and sharp taste, the dry residue is not less than 95%, the content of gingerols is 5%. Screening of the effective dose of Ginger extract for hypoglycemic action was performed on intact normoglycemic rats in a dose range of 10–150 mg/kg. As a reference, the compound «Arfazetin» and metformin were used. The possible hypoglycemic effect of Ginger extract was determined after its single fasting intragastric administration. The antihyperglycemic properties of Ginger extract were studied under conditions of 20-day administration with intraperitoneal and oral glucose tolerance tests on the dynamics of glycemia and areas under glycemic curves. A single introduction of Ginger extract in a dose range of 10–150 mg/kg and comparison drug «Arfazetine» did not show a hypoglycemic effect when fasting. Against the background of 20-day extract of ginger administration at intraperitoneal glucose tolerance test it was revealed that the pronounced antihyperglycemic effect of Ginger extract begins to manifest at a dose of 80 mg/kg (40%) and remains consistently the same when a high dose is administered – 150 mg/kg (41%). On the model of oral glucose tolerance test, when using extract of ginger in doses of 80 and 100 mg/kg, almost identical oppression of acute hyperglycemia was registered at 40 and 38% at the 30th minute of the test. This indicates a pronounced antihyperglycemic effect of the study agent. In terms of antihyperglycemic activity, extract of ginger at a dose of 80 mg/kg is not inferior to metformin and significantly exceeds the compoud «Arfazetin» by 1.3 times. The obtained results are the basis for in-depth study of Ginger extract at a dose of 80 mg/kg as antidiabetic agent

A Double-Blind, Randomized, Placebo-Controlled Clinical Trial on Benfotiamine Treatment in Patients With Diabetic Nephropathy

OBJECTIVE - To investigate the effect of benfotiamine on urinary albumin excretion (UAE) and the tubular damage marker kidney injury molecule-1 (KIM-1) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS - Patients with type 2 diabetes and UAE equivalent to 15-300 mg/24 h, despite ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), were randomly assigned to 12 weeks of benfotiamine (900 mg/day) (n = 39) or placebo (n = 43). RESULTS - Compared with placebo, benfotiamine treatment resulted in significant improvement of thiamine status (P <0.001). Benfotiamine treatment did not significantly decrease 24-h UAE or 24-h KIM-1 excretion. CONCLUSIONS - In patients with type 2 diabetes and nephropathy, high-dose benfotiamine treatment for 12 weeks in addition to ACE-Is or ARBs did not reduce UAE or KIM-1 excretion, despite improvement of thiamine status

Endoscopic Resection Without Subsequent Ablation Therapy for Early Barrett's Neoplasia:Endoscopic Findings and Long-Term Mortality

INTRODUCTION: After endoscopic resection (ER) of neoplasia in Barrett's esophagus (BE), it is recommended to ablate the remaining BE to minimize the risk for metachronous disease. However, we report long-term outcomes for a nationwide cohort of all patients who did not undergo ablation of the remaining BE after ER for early BE neoplasia, due to clinical reasons or performance status. METHODS: Endoscopic therapy for BE neoplasia in the Netherlands is centralized in 8 expert centers with specifically trained endoscopists and pathologists. Uniformity is ensured by a joint protocol and regular group meetings. We report all patients who underwent ER for a neoplastic lesion between 2008 and 2018, without further ablation therapy. Outcomes include progression during endoscopic FU and all-cause mortality. RESULTS: Ninety-four patients were included with mean age 74 (± 10) years. ER was performed for low-grade dysplasia (LGD) (10%), high-grade dysplasia (HGD) (25%), or low-risk esophageal adenocarcinoma (EAC) (65%). No additional ablation was performed for several reasons; in 73 patients (78%), the main argument was expected limited life expectancy. Median C2M5 BE persisted after ER, and during median 21 months (IQR 11-51) with 4 endoscopies per patient, no patient progressed to advanced cancer. Seventeen patients (18%) developed HGD/EAC: all were curatively treated endoscopically. In total, 29/73 patients (40%) with expected limited life expectancy died due to unrelated causes during FU, none of EAC. CONCLUSION: In selected patients, ER monotherapy with endoscopic surveillance of the residual BE is a valid alternative to eradication therapy with ablation

Comparison of Methods for Renal Risk Prediction in Patients with Type 2 Diabetes (ZODIAC-36)

BACKGROUND: Patients with diabetes are at high risk of death prior to reaching end-stage renal disease, but most models predicting the risk of kidney disease do not take this competing risk into account. We aimed to compare the performance of Cox regression and competing risk models for prediction of early- and late-stage renal complications in type 2 diabetes. METHODS: Patients with type 2 diabetes participating in the observational ZODIAC study were included. Prediction models for (micro)albuminuria and 50% increase in serum creatinine (SCr) were developed using Cox regression and competing risk analyses. Model performance was assessed by discrimination and calibration. RESULTS: During a total follow-up period of 10 years, 183 out of 640 patients (28.6%) with normoalbuminuria developed (micro)albuminuria, and 22 patients (3.4%) died without developing (micro)albuminuria (i.e. experienced the competing event). Seventy-nine out of 1,143 patients (6.9%) reached the renal end point of 50% increase in SCr, while 219 (19.2%) died without developing the renal end point. Performance of the Cox and competing risk models predicting (micro)albuminuria was similar and differences in predicted risks were small. However, the Cox model increasingly overestimated the risk of increase in SCr in presence of a substantial number of competing events, while the performance of the competing risk model was quite good. CONCLUSIONS: In this study, we demonstrated that, in case of substantial numbers of competing events, it is important to account for the competing risk of death in renal risk prediction in patients with type 2 diabetes

Sex Differences in Neoplastic Progression in Barrett's Esophagus:A Multicenter Prospective Cohort Study

Recommendations in Barrett’s esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as highgrade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11–4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33–10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29–0.95) and HGD (AR 0.40, 95% CI 0.19–0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models

Serum Peroxiredoxin 4:A Marker of Oxidative Stress Associated with Mortality in Type 2 Diabetes (ZODIAC-28)

BACKGROUND: Oxidative stress plays an underlying pathophysiologic role in the development of diabetes complications. The aim of this study was to investigate peroxiredoxin 4 (Prx4), a proposed novel biomarker of oxidative stress, and its association with and capability as a biomarker in predicting (cardiovascular) mortality in type 2 diabetes mellitus. METHODS: Prx4 was assessed in baseline serum samples of 1161 type 2 diabetes patients. Cox proportional hazard models were used to evaluate the relationship between Prx4 and (cardiovascular) mortality. Risk prediction capabilities of Prx4 for (cardiovascular) mortality were assessed with Harrell's C statistic, the integrated discrimination improvement and net reclassification improvement. RESULTS: Mean age was 67 and the median diabetes duration was 4.0 years. After a median follow-up period of 5.8 years, 327 patients died; 137 cardiovascular deaths. Prx4 was associated with (cardiovascular) mortality. The Cox proportional hazard models added the variables: Prx4 (model 1); age and gender (model 2), and BMI, creatinine, smoking, diabetes duration, systolic blood pressure, cholesterol-HDL ratio, history of macrovascular complications, and albuminuria (model 3). Hazard ratios (HR) (95% CI) for cardiovascular mortality were 1.93 (1.57 - 2.38), 1.75 (1.39 - 2.20), and 1.63 (1.28 - 2.09) for models 1, 2 and 3, respectively. HR for all-cause mortality were 1.73 (1.50 - 1.99), 1.50 (1.29 - 1.75), and 1.44 (1.23 - 1.67) for models 1, 2 and 3, respectively. Addition of Prx4 to the traditional risk factors slightly improved risk prediction of (cardiovascular) mortality. CONCLUSIONS: Prx4 is independently associated with (cardiovascular) mortality in type 2 diabetes patients. After addition of Prx4 to the traditional risk factors, there was a slightly improvement in risk prediction of (cardiovascular) mortality in this patient group

A deep learning system for detection of early Barrett's neoplasia:a model development and validation study

BACKGROUND: Computer-aided detection (CADe) systems could assist endoscopists in detecting early neoplasia in Barrett's oesophagus, which could be difficult to detect in endoscopic images. The aim of this study was to develop, test, and benchmark a CADe system for early neoplasia in Barrett's oesophagus.METHODS: The CADe system was first pretrained with ImageNet followed by domain-specific pretraining with GastroNet. We trained the CADe system on a dataset of 14 046 images (2506 patients) of confirmed Barrett's oesophagus neoplasia and non-dysplastic Barrett's oesophagus from 15 centres. Neoplasia was delineated by 14 Barrett's oesophagus experts for all datasets. We tested the performance of the CADe system on two independent test sets. The all-comers test set comprised 327 (73 patients) non-dysplastic Barrett's oesophagus images, 82 (46 patients) neoplastic images, 180 (66 of the same patients) non-dysplastic Barrett's oesophagus videos, and 71 (45 of the same patients) neoplastic videos. The benchmarking test set comprised 100 (50 patients) neoplastic images, 300 (125 patients) non-dysplastic images, 47 (47 of the same patients) neoplastic videos, and 141 (82 of the same patients) non-dysplastic videos, and was enriched with subtle neoplasia cases. The benchmarking test set was evaluated by 112 endoscopists from six countries (first without CADe and, after 6 weeks, with CADe) and by 28 external international Barrett's oesophagus experts. The primary outcome was the sensitivity of Barrett's neoplasia detection by general endoscopists without CADe assistance versus with CADe assistance on the benchmarking test set. We compared sensitivity using a mixed-effects logistic regression model with conditional odds ratios (ORs; likelihood profile 95% CIs).FINDINGS: Sensitivity for neoplasia detection among endoscopists increased from 74% to 88% with CADe assistance (OR 2·04; 95% CI 1·73-2·42; p&lt;0·0001 for images and from 67% to 79% [2·35; 1·90-2·94; p&lt;0·0001] for video) without compromising specificity (from 89% to 90% [1·07; 0·96-1·19; p=0·20] for images and from 96% to 94% [0·94; 0·79-1·11; ] for video; p=0·46). In the all-comers test set, CADe detected neoplastic lesions in 95% (88-98) of images and 97% (90-99) of videos. In the benchmarking test set, the CADe system was superior to endoscopists in detecting neoplasia (90% vs 74% [OR 3·75; 95% CI 1·93-8·05; p=0·0002] for images and 91% vs 67% [11·68; 3·85-47·53; p&lt;0·0001] for video) and non-inferior to Barrett's oesophagus experts (90% vs 87% [OR 1·74; 95% CI 0·83-3·65] for images and 91% vs 86% [2·94; 0·99-11·40] for video).INTERPRETATION: CADe outperformed endoscopists in detecting Barrett's oesophagus neoplasia and, when used as an assistive tool, it improved their detection rate. CADe detected virtually all neoplasia in a test set of consecutive cases.FUNDING: Olympus.</p

Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects

Background: High dose oral thiamine may have a role in treating diabetes, heart failure, and hypermetabolic states. The purpose of this study was to determine the pharmacokinetic profile of oral thiamine hydrochloride at 100 mg, 500 mg and 1500 mg doses in healthy subjects. Methods: This was a randomized, double-blind, single-dose, 4-way crossover study. Pharmacokinetic measures were calculated. Results: The $AUC_{0-10 hr}$ and $C_{max}$ values increased nonlinearly between 100 mg and 1500 mg. The slope of the $AUC_{0-10 hr}$ vs dose, as well as the $C_{max}$ vs dose, plots are steepest at the lowest thiamine doses. Conclusion: Our study demonstrates that high blood levels of thiamine can be achieved rapidly with oral thiamine hydrochloride. Thiamine is absorbed by both an active and nonsaturable passive process