Significant Increase In Efficacy Research Articles

Analysis of Different Treatment Methods for Breast Cancer

This research discusses the mechanisms of current medical treatments for breast cancer and a brief analysis of the treatments. The aim of this research is to present the different cancer therapies and to select the most promising and promising therapies for breast cancer based on the performance of each therapy, where chemotherapy, radiotherapy, and immunotherapy for breast cancer are discussed. By analyzing the various therapies, it is concluded that all three therapies selected for discussion have shown a significant increase in efficacy over their traditional counterparts, but at the same time, the risks and potential shortcomings of the newer therapies have been demonstrated in experimental trials. Through the analysis of this research, it is hoped that there will be a combination of techniques and breakthroughs in therapies for breast cancer. Each therapy has its own shortcomings, and the combination of chemotherapy, radiation, and immunotherapy with current cancer therapies will be the future of cancer breakthroughs.

Abstract 684: DT-9045, a novel PAR2 inhibitor with best-in-class properties that reduces resistance to both EGFR-targeting therapies and immunotherapy in oncology models

Abstract Protease-activated receptor 2 (PAR2) is a promising therapeutic target in oncology and immuno-oncology. It is upregulated and associated with poor prognosis in several cancer types. A pan-cancer meta-analysis showed that PAR2 is one of the genes most significantly associated with resistance to immune checkpoint blockade (ICB) and T cells dysfunction in cancer patients. Mechanistically, being expressed by various cells of the tumor microenvironment, PAR2 promotes both survival and proliferation of cancer cells and dampens the anti-cancer immune response. Domain Therapeutics has developed a novel PAR2 inhibitor, DT-9045, with best-in-class properties. Indeed, compared to its most advanced competitors, DT-9045 is a small molecule, orally bioavailable, insurmountable, biased, and active in tumor-like conditions (i.e. acidic pH and high level of activating proteases). This compound is also highly potent and selective on PAR2. Pharmacokinetic properties are suitable with a once-a-day oral administration. In vitro, DT-9045 completely prevented PAR2-mediated resistance to EGFR-targeting drugs. In vivo, its combination with anti-PD1 therapy showed a significant increase in efficacy over monotherapies in preclinical syngeneic mouse cancer models. This result was similar to the one observed in PAR2 knockout mice, indicating that oral administration of DT-9045 induces a complete inhibition of the receptor. We have further demonstrated that treatment with a PAR2 inhibitor enhances dendritic cell-mediated T cell activation and intratumoral infiltration of CD4+ and CD8+ T cells as well as a decrease in M2 macrophage infiltration. In conclusion, Domain Therapeutic has identified a novel PAR2 inhibitor, DT-9045, with clear competitive advantages. This preclinical candidate has shown strong potency in alleviating the resistance to both EGFR-targeting therapies and immunotherapy in preclinical cancer models. IND-enabling studies are currently ongoing to bring this new hope for cancer patients to the clinic. Citation Format: Thibaut Brugat, Maleck Kadiri, Samya Aouad, Anne-Laure Blayo, Baptiste Rugeri, Antoine Mousson, Aurélie Janvier, Edith Steinberg, Luc Baron, Mandy Recolet, Xavier Wirth, Maria Jesus Garcia-Leon, Quentin Ruet, Meriem Semache, Laurent Sabbagh, Orphée Blanchard, Christel Franchet, Stanislas Mayer, John Stagg, Nathalie Lenne, Stephan Schann. DT-9045, a novel PAR2 inhibitor with best-in-class properties that reduces resistance to both EGFR-targeting therapies and immunotherapy in oncology models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 684.

EFFICACY OF LACTOSE-FREE FORMULA AS A 24-HOUR MANAGEMENT APPROACH FOR ACUTE DIARRHEA AMONG CHILDREN

Background: Diarrhea continues to be a prominent contributor to morbidity and mortality among young children under five years, especially in developing nations. Secondary lactose intolerance is a significant complication that can arise from acute diarrhea. However, it can be effectively managed with lactose-free formula.
 Objective: This study aimed to compare the rate of diarrhea resolution within a 24-hour period among children receiving lactose-free formula and those receiving lactose-containing formula.
 Methods: This retrospective cohort study took place at Naresuan University Hospital and included 153 children aged between one month and five years admitted with acute diarrhea. Participants with bloody mucous diarrhea suspected to be bacterial in nature, positive stool culture, breastfeeding and chronic diarrhea (including cow’s milk protein allergy and inflammatory bowel disease) were excluded. We compared the effectiveness of lactose-free formula (n=48) and lactose-containing formula in improving clinical diarrhea within a 24-hour (n=105).
 Results: The study findings indicated the lactose-free formula group demonstrated a statistically significant increase in efficacy, with a 3.90 fold improvement in diarrhea within 24 hours compared with that of the group receiving lactose-containing formula. These results were obtained after the confounding factors were adjusted using multivariable regression analysis. The adjusted relative risk (RR) for a 24-hour improvement in diarrhea was 3.90 (95% CI: 1.91-7.95). However, this study encountered limitations regarding the sample size and accurate measurement of stool output.
 Conclusion: Lactose-free formula showed the potential for greater effectiveness in improving acute diarrhea within a 24-hour timeframe compared with lactose-containing formula.

Deep Learning Driven Instinctive Surveillance

It is a very boring and laborious job providing observation security. In order to determine whether the exercises that were caught were unusual or suspicious, a labour force is needed. Here, we’ll put together a structure to automate the task of reviewing video reconnaissance. We will regularly review the camera feed to look for any unusual activities like surprising or suspicious ones. and an automatic acknowledgment will be sent to the user with an alert email along with the suspicious frames and SMS to mobile number. Deep learning computations for deep reconnaissance have improved from earlier encounters. These developments have revealed a key pattern in thorough reconnaissance and promise a significant increase in efficacy. Deep observation is typically used for things like identifying evidence of burglary, finding violence, and recognising explosion potential. We will propose a spatio-temporal auto-encoder for this project that relies on a 3D convolutional brain structure. The decoder then reproduces the edges after the encoder section has removed the spatial and transient data. By recording the recreation misfortune using the Euclidean distance between the original and replicated batch, the odd occurrences are distinguished.

A Single Session of Spinal Decompression with Oscillation and Videofluoroscopy

Background: Computerized spinal decompression using the intervertebral differential dynamics (IDD) therapy protocol has achieved 86–92% positive results in reducing back pain. There are many causes of back pain, and one of the most common is a degenerative disc. The etiology of a degenerative disc is not completely understood, but it can be related to acute injuries, repetitive stress, nutrition, genetic factors, and oxidative stress1. Standard of care may include physical therapy or manipulation to introduce movement to the spinal vertebrae. IDD Therapy® uses a calculated, sinusoidal, logarithmic primary waveform to separate the spinal vertebrae. More recent studies have shown that the addition of a secondary waveform gives a significant increase in efficacy. We observed these effects on the spine during an IDD Therapy® session. Methods: Images of the intervertebral space were taken by videofluoroscopy during the IDD Therapy® session. Results: The expected separation of L5-S1 was achieved. We also noted the separation profile of the vertebrae was uniquely uniform despite the graduated pressures, particularly when the secondary oscillation waveform was introduced. L5-S1 separation was 1 mm in size, and the anterior–posterior correlation was significant (p<0.05). Conclusion: Active oscillatory signaling introduced during the high-tension period of treatment may lead to more compliant muscle re-education and thus enhanced uniform separation of the vertebrae. We believe that IDD Therapy® using Accu-Spina® may achieve 92% positive results because the secondary oscillatory signal induces mechanotransduction of mechanical stimuli into electrochemical activity at the cellular level. Further research will lead to greater confidence and further exploration of mechanotransduction in intradiscal cellular tissues.

DDDR-25. CO-INHIBITION OF KINASE SIGNALING PATHWAYS AND EPIGENETIC REGULATORS OVERCOMES COMPENSATORY EFFECTS IN PEDIATRIC HIGH-GRADE GLIOMAS

Abstract Pediatric high-grade gliomas (pHGG) confer poor survival outcomes with minimal treatment options due to a high rate of therapeutic resistance and few surgical options. One subgroup of pHGG is diffuse intrinsic pontine glioma (DIPG). Patient-derived cell lines, such as SU-DIPG-XIII, SU-DIPG-VI, and SU-DIPG-IV, recapitulate epigenetic mutations seen in patients. In these lines, lysine-specific demethylase 1 (LSD1) is overexpressed and knockdown/inhibition slows growth, therefore, optimizing LSD1 inhibitor treatment regimens is promising. In other models, MEK kinase activation acts as a mechanism of resistance to LSD1 inhibitors. This is relevant to DIPG due to the frequency of dysregulated and mutated upstream kinase pathways. Thus, we sought to identify the connection between LSD1 and kinase signaling as a therapeutic co-inhibition strategy in DIPG. Pharmacologically relevant catalytic LSD1 inhibitors were assessed using the alamarBlue viability assay and demonstrated wide ranges of IC₅₀ values with ORY-1001(19 μM to > 150 μM), ORY-2001( > 50 μM), GSK-LSD1(134 μM to > 500 μM), and IMG-7289(1.6 μM-179 μM) in the SU-DIPG lines. Resistance mechanisms from kinase modulation were investigated via Western Blot to determine if kinase inhibition could sensitize these cells to LSD1 inhibition. We discovered that LSD1 inhibition caused an unexpected increase in pAKT and pERK, suggesting enhanced activity of protumorigenic kinases. To overcome kinase activation from LSD1 inhibition, MEK or PI3K inhibitors, including selumetinib, trametinib, and BKM120, were tested. A novel dual kinase inhibitor directed against EGFR and PI3K, MTX-241F, was also assessed. Several combinations caused a significant increase in efficacy measured by cell viability. We further observed that the addition of kinase inhibitors with LSD1 inhibition decreased phosphorylated kinases. Overall, the combination enhanced in vitro efficacy in contrast to single-agent inhibition supporting an interplay between LSD1 and kinase signaling in pHGG. Future studies will assess this combination utilizing orthotopic xenograft models of DIPG

Synergism of Adjuvants Mixed With Spinetoram for the Management of Bean Flower Thrips, Megalurothrips usitatus (Thysanoptera: Thripidae) in Cowpeas.

The bean flower thrips, Megalurothrips usitatus (Bagnall) is an economically important insect pest of cowpea, Vigna unguiculata (L.) Walp in south China. Spinetoram is a newly available commercial active ingredient in the spinosyn mode of action group of insecticides that has been recommended for thrips management in China. In this study, the toxicity and efficacy of spinetoram for controlling M. usitatus were evaluated and compared to six other conventional insecticides. In addition, the synergistic effects of adjuvants (Silwet 806, Silwet 618, AgroSpred 910, and AgroSpred Prime) mixed with spinetoram for thrips control on cowpea were evaluated in both the laboratory and the field. Results of this study showed that spinetoram had higher toxicity and field efficacy of M. usitatus than other tested insecticides. A significant increase in efficacy was observed when spinetoram was applied at a recommended rate of 0.67 ml/L, mixed with Silwets (806 and 618) at the rate of 0.5 ml/L. Reductions of 50% and 40% in thrips infestation in the field over treatments without adjuvants were observed 3- and 7-days posttreatments, respectively. However, no significant reduction of M. usitatus was recorded when spinetoram was mixed with AgroSpreds (910 and Prime). Furthermore, no significant differences were found in thrips infestation between spinetoram sprayed alone at the rate of 0.67 ml/L and a reduced rate of spinetoram (0.45 ml/L) mixed with Silwets (806 and 618). The current research shows that Silwets mixed with spinetoram has a synergistic effect in the management of thrips.

Abstract 1050: Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia

Abstract Acute Myeloid Leukemia (AML) is the most common and aggressive acute leukemia in adults, with a 25% 5-year survival rate. FLT3 is the most frequently mutated gene in AML. About 25% of AML patients harbor FLT3 internal tandem duplication (ITD) mutations, and about 8 % of patients harbor FLT3 tyrosine kinase domain (TKD) mutations. Both FLT3-ITD and FLT3-TKD mutations constitutively activate the protein, which causes poor survival. Gilteritinib is a highly potent and selective oral FLT3 inhibitor recently approved by the FDA. Although gilteritinib showed strong single agent activity in AML patients with FLT3 mutations, the development of gilteritinib resistance limits the long-term efficacy of this treatment, indicating that combination therapy may be advantageous for AML patients with FLT3 mutations. FLT3 mutations are known to be anti-apoptotic. Myeloid cell leukemia-1 (MCL-1), an anti-apoptotic protein, expressed in a large percentage of the AML patient population, plays a critical role in AML cell survival and drug resistance. AMG 176 is a potent, selective and orally bioavailable MCL-1 inhibitor, which induces rapid commitment to apoptosis in AML. Here we demonstrated that AMG 176 and gilteritinib combination treatment synergistically targeted FLT3-ITD mutated AML. A strong synergistic effect (Combination index <0.2) was observed in two FLT3-ITD mutated AML cell lines treated with the AMG 176 plus gilteritinib combination. Increased Bcl-2-like protein 11 (BIM) expression and decreased BIM/MCL-1 interaction was observed under the combination treatment, coupled with a significant increase in apoptosis. In the MV4-11 AML xenograft model, mice treated with two cycles of AMG 176 (2 days on 5 days off) at 30 mg/kg or with 3 mg/kg gilteritinib daily showed 76% or 74% tumor growth inhibition respectively. A statistically significant increase in efficacy was observed in the combination treatment group, with 92.8% tumor regression, including 50% of mice being tumor free. No significant difference in body weight was found between groups. Our results show that AMG 176 plus gilteritinib treatment was effective and well tolerated in mouse models of AML, which supports further evaluation in a clinical setting. Citation Format: Xiaoyue Chen, Sean Caenepeel, Brian Belmontes, Patricia L. McElroy, Karen Rex, Tao Osgood, Paul Hughes. Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1050.

A 100-fold increasing in measles virus titer following enrichment of culture medium with MgSO4

Measles is a contagious disease which causes more than 140,000 deaths per year. The aim of this research was to increase the titer of harvested Measles virus during its propagation in cell culture. For this purpose, the effect of Magnesium Sulfate on titer of Measles virus was evaluated. Specific concentrations of magnesium sulfate salt along with measles virus of AIK-C strain (vaccine strain) were added into chick embryos cell culture medium. Then at the specific times interval the virus concentration in the control and test samples were determined by CCID50 method. Finally the obtained results were compared by Real Time _RT PCR method. The results showed that, MgSo4 increases the titer of Measles virus in the harvested suspensions. The mean increase in viral titer in comparison to the control was determined as 2.3 Log (in macrotitration method) and 2.17 Log (in microtitration method). Also there were significant correlation between CCID50 method and Real Time _RT PCR. In this research, the titer of harvested Measles virus was increased by 100 fold. This method making a significant increase in efficacy of the virus propagation process, so, the expenses of vaccine production will be decreased.

Semi-Industrial Fluorination of β-Keto Esters with SF4: Safety vs Efficacy

The possibility of deoxofluorination of β-keto esters using SF4 was investigated. The scope and limitation of the reaction were determined. The efficient method for the synthesis of β,β-difluorocarboxylic acids was elaborated based on the reaction. The set of mentioned acids, being the perspective building blocks for medicinal chemistry, were synthesized on multigram scale. The safety of SF4 use was discussed. The described method does not improve upon the safety of using SF4, but practical recommendations for working with the reagent are proposed. Despite the hazards of using toxic SF4, a significant increase of efficacy in the synthesis of medicinal-chemistry-relevant building blocks, based on the reaction, in comparison with earlier described approaches is shown.

The effect of curcumin in antitumor photodynamic therapy: In vitro experiments with Caco-2 and PC-3 cancer lines.

Photodynamic Therapy (PDT) is a promising antitumor and anti-bacterial treatment method for its high selectivity, non-invasiveness, and minimal side effects. However, cellular mechanisms may lead to PDT resistance and thus effect efficacy. The aim of this study is to test whether Curcumin, which is a non-toxic natural compound that has antitumor characteristics, can increase PDT efficacy by overcoming the resistance of cancer cells. 5-ALA mediated PDT was tested on two cell lines, PC-3 and Caco-2. Curcumin toxicity was evaluated at different concentrations. The determined PDT doses were applied to the cell lines together with two different Curcumin concentrations. Cell viability was evaluated by MTT assay, 24 hs after the treatments. Results were evaluated using One-Way ANOVA followed by post-hoc tests. Using non-toxic doses of Curcumin resulted in a significant decrease in PDT resistance in Caco-2 cells and thus increased the efficacy of 5-ALA mediated PDT, but not on PC-3. Adding Curcumin to 5-ALA mediated PDT led to more effective results on Caco-2 with a 62.4% decrease in cell viability. On the other hand, adding Curcumin to 5-ALA mediated PDT on PC-3 cells didn't produce statistically significant increase in efficacy with a 36% decrease in cell viability. 5-ALA mediated PDT combined with Curcumin synergistically enhanced antitumor PDT efficacy on Caco-2, which is considered a highly resistive cancer cell line.

Abstract P6-20-11: The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, enhances antitumor efficacy of paclitaxel and Nab-paclitaxel in TP53 wild-type MCF-7 breast cancer models

Abstract Background: MDMX and MDM2 are endogenous inhibitors of the p53 tumor suppressor protein. MDMX levels are frequently elevated in luminal breast cancer, which generally expresses wild-type p53. ALRN-6924, an α-helical stapled peptide, is the first and only dual inhibitor of MDMX and MDM2 currently in clinical trials for solid tumors and hematological malignancies. We sought to determine the antitumor efficacy of the combination of ALRN-6924 with taxanes in models of human breast cancer. Methods: Sulforhodamine B colorimetric assay was used to assess the cytotoxicity of the combination of ALRN-6924 with taxanes in vitro. Athymic nude mice were implanted with MCF-7 tumors and treated for four weeks with ALRN-6924 alone and in combination with paclitaxel in cremaphor (Taxol®, study #1) or a nanoparticle-albumin-bound (nab) formulation (Abraxane®, study #2). In study #1, ALRN-6924 (5, 10 mg/kg) was dosed twice weekly and paclitaxel (10, 15 mg/kg) was dosed weekly, with paclitaxel administered 6 h prior to ALRN-6924. In study #2, ALRN-6924 alone (5 mg/kg) was dosed twice weekly while nab-paclitaxel (15 mg/kg) was administered weekly in combination at -24h, -6h, 0h, +6h, or +24h relative to ALRN-6924 administration. Results: ALRN-6924 was found to have synergistic activity with paclitaxel in both MCF-7 and ZR-75-1 cell lines in vitro (Combination index: 0.874 and 0.323 respectively). In in vivo study #1, the combination of ALRN-6924 and paclitaxel significantly inhibited MCF-7 tumor growth compared to either agent alone (p<0.005). Paclitaxel 15 mg/kg + ALRN-6924 5 mg/kg resulted in the greatest tumor inhibition with average tumor size decreased by 13% at four weeks versus the starting size. In study #2, the combination of nab-paclitaxel with ALRN-6924 administered -6h to +24h relative to nab-paclitaxel resulted in improved efficacy over either single agent and a significant increase in the number of tumor regressions (up to 6/10 with 3 consecutive measurements <50% of starting volume) compared to nab-paclitaxel alone (1/10, p<0.005). When ALRN-6924 was administered 24h prior to nab-paclitaxel, there was a marked decrease in efficacy and no tumor regressions were observed. In both studies, drug treatments were well tolerated with no significant weight loss in mice. Conclusion: The significant increase in efficacy observed with ALRN-6924 in combination with paclitaxel supports further evaluation in patients with breast cancer. Citation Format: Pairawan SS, Yuca E, Evans K, Annis A, Narasimhan N, Sutton D, Carvajal LA, Ren J-G, Santiago S, Guerlavais V, Akcakanat A, Tapia C, Illeana Dumbrava EE, Aivado M, Meric-Bernstam F. The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, enhances antitumor efficacy of paclitaxel and Nab-paclitaxel in TP53 wild-type MCF-7 breast cancer models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-11.

The efficacy of Xue Fu Zhu Yu prescription for hyperlipidemia: A meta-analysis of randomized controlled trials

Hyperlipidemia is rampant as a crucial risk factor for cardiovascular diseases. Xue Fu Zhu Yu (XFZY), a prescription formula in traditional Chinese medicine, is well-known for treating hyperlipidemia. Herein we conducted meta-analysis and assessed the efficacy of XFZY prescription as mono or adjunctive therapy in patients with hyperlipidemia. Databases including Medline, Cochrane Library, Embase, CNKI, Wanfang Data and VIP Information were comprehensively investigated via searching keywords “Xuefuzhuyu”, “Xuefu Zhuyu”, “Xue Fu Zhu Yu”, “Xuefu-Zhuyu” or “XFZY” in combination with “hyperlipidemia” and “dyslipidemia”. Efficacy, methodological quality, and publication bias of recruited trials on XFZY prescription were also assessed. Review Manager version 5.3 software was used for statistical analysis. Twelve trials involving 1305 participants all reported in Chinese were enrolled and, based on our analysis, significant increase of efficacy in XFZY prescription groups compared to control groups was observed, and there was either significance or non-significance of differences in regulating the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). This meta-analysis preliminarily demonstrated that XFZY prescription is effective for treating hyperlipidemia, but due to the poor methodological quality of most analyzed trials, conclusion should be cautiously summarized. Thoroughly designed, large-scale and multicenter trials are needed to estimate efficacy and safety of XFZY prescription for hyperlipidemia in the future.

Efficacy of chemical products and epiphytic bacteria in control of fire blight (Erwinia amylovora)

In model tests carried out in a greenhouse on apple trees, it was shown that in conditions of high infection pressure of E. amylovora, the one-off, preventive use of Aliette 80WG during full bloom was effective in reducing blossom blight in the range of 60-70%. There was no significant increase in efficacy after using this product twice in comparison to single application. However, Aliette turned out to be ineffective in the protection of terminal shoots. High efficacy, both in protecting blossoms and apple shoots, was shown by a cooper-based formulation Miedzian 50WP, but it caused some phytotoxicity on flower petals. Also in the test on slices of pear fruitlets, this product caused significant ressetting. Overall, the highest efficacy among the different formulations and bacterial isolates tested was recorded when the pear fruitlet slices were treated with the bacterial isolate A15 (Pantoea agglomerans) (96%); other effective products were the antibiotic-based Kasumin 2L (94%) and Miedzian 50WP (89%). It is noteworthy that Controlphyt Cu, a foliar and soil fertilizer containing Cu, showed quite high efficacy – up to 71% when applied at the concentration of 0.4% and 41% at 0.2%. Key words: fosetyl aluminium, copper, kasugamycin, biocontrol, apple, pear.

SPECIFICS OF ANTIHYPERTENSION THERAPY IN HYPERTENSIVES OF VARIOUS CARDIOVASCULAR RISK (BY THE REGISTRY OF CHRONIC NON-COMMUNICABLE DISEASES IN TYUMENSKAYA OBLAST)

Aim. To assess the specifics of antihypertension therapy (AHT) in hypertensives of various cardiovascular risk, in the registry of chronic non-communicable diseases in Tyumenskaya oblast.Material and methods. A random sample studied, of 1704 patients with hypertension, inhabitants of Tyumenskaya oblast (region), ascribed to dispensary follow-up. Mean age 62±7,5 y.o. Of those 31,5% (n=537) males. The prevalence and efficacy of AHT assessed according to cardiovascular risk level. The significance was evaluated with the criteria χ2.Results. AHT was characterized by the growth of the frequency of treatment approaches with cardiovascular risk consideration. Regular treatment took 33,9% patients of low and moderate risk vs 41,3% of high and very high (p<0,01). In the male group such tendency also took place. Gender specifics of AHT was characterized by that in the groups of high and very high risk females took medications significantly more commonly than males — 46,6% vs 29,1% in high risk group (p<0,01) and 47,5% vs 30% in very high risk group (p<0,01). With the increase of the risk level, there was decline of treatment efficacy — from 95% in low risk group to 32,5% in very high risk group; 53,1% of the participants were taking monotherapy, 32,9% — two drugs, 14,0% — ≥3 drugs. With the increase of risk grade there is tendency to increase of combinational AHT, however with no significant increase of efficacy. Treatment efficacy in high and very high risk patients comparing to patients with low and moderate risk was significantly lower — 33,1% vs 69,7% (p<0,01), respectively. Statins intake among the high and very high risk patients was 10,6-11,0% males and 7,8% females (p<0,05).Conclusion. AHT in hypertensives in Tymenskaya oblast, under dispensary follow-up, is characterized by insufficient usage of combinational drugs. With the raise of cardiovascular risk there is tendency to higher rate of combinational AHT. However there is no significant increase in efficacy of treatment with the increase of medications number. A very low rate of statins intake is noted. The obtained specifics witness for the necessity to optimize AHT among the high and very high risk patients — inhabitants of Tyumenskya oblast.

Роль препаратов висмута в повышении эффективности эрадикации инфекции Helicobacter pylori

Aim of review. To demonstrate modern potential of bismuth agents administration for increasing of Helicobacter pylori (H. pylori) eradication efficacy. Summary. Prevention of peptic ulcer and stomach cancer makes eradication of H. pylori infection more and more important. At the same time efficacy of some eradication modes, first of all - that of standard triple therapy, steadily decreases because of growing antibiotic resistance of H. pylori strains, first of all - clarithromycin resistance. The concept that empirical prescription of standard triple therapy should be abandoned in favor of initial H. pylori clarithromycin-resistance testing by culture or real-time polymerase chain reaction became widely accepted. Bismuth-based quadrotherapy mainly - with bismuth tripotassium dicitrate (BTD) is alternative to standard triple mode therapy nowadays. Potential of BTD combination not only to tetracycline but to other antibiotics as well was demonstrated. Addition of BTD to triple therapy containing clarithromycin, levofloxacin, metronidazole allows to increase eradication efficacy for 30-40% at H. pylori-resistant strains. Absence of H. pylori resistance development to BTD, combined antibacterial and cytoprotective effects as well as good tolerance are important advantages of the drug. Conclusion. Addition of BTD to triple H. pylori eradication modes, that include different antibiotics (clarithromycin, levofloxacin and metronidazole) provide significant increase in efficacy of eradication at antibioticresistant Helicobacter pylori strains.

Design, synthesis and biological activity evaluation of novel 4-subtituted 2-naphthamide derivatives as AcrB inhibitors

A novel series of 4-substituted 2-naphthamide derivatives were designed, synthesized and evaluated for their biological activity. In particular, the ability of the compounds to potentiate the action of antibiotics, to inhibit Nile Red efflux and to target AcrB specifically was investigated. The results indicated that most of the 4-substituted 2-naphthamide derivatives were able to synergize with the antibiotics tested, and inhibit Nile Red efflux by AcrB in the resistant phenotype. Subsequent exclusion of compounds with off target effects such as outer- or inner membrane permeabilization identified compounds 7c, 7g, 12c, 12i and 13g as efflux pump inhibitors (EPIs). Particularly, compounds 7c, 7g and 12i were found to be the most potent EPIs, which synergized with the two substrates tested at lower concentrations than that of parent A3, demonstrating an improvement in potency as compared to A3. Additionally, when the outer membrane of E. coli was permeabilized, compound 12c displayed a huge increase in efficacy and was able to synergize with erythromycin at a concentration that was 16 times lower than that of the parent A3. Hence we were able to design and synthesize compounds that displayed significant increase in efficacy as EPIs against AcrB.

Comparison of the newer preventive therapies on remineralisation of enamel in vitro

ObjectivesTo investigate in vitro the effect of MI Paste, MI Paste Plus and 2800ppm fluoride (F) toothpaste (TP) on the remineralisation of enamel subsurface lesions and to compare these to the effect of 1450ppm and 0ppm F toothpastes. MethodsEnamel subsurface lesions were created in bovine enamel slabs (n=120) which were assigned randomly to five groups; (1) 0ppm F TP, (2) 1450ppm F TP, (3) 2800ppm F TP, (4) 1450ppm F TP+MI Paste (Tooth Mousse-TM,10% w/v CPP-ACP) and (5) 1450ppm F TP+MI Paste Plus (Tooth Mousse Plus,10% w/v CPP-ACP, 900ppm F as 0.2% w/w sodium fluoride). The enamel slabs were subjected to a pH cycling regimen for 21days. Quantitative Light-induced Fluorescence (QLF) images were taken and analysed. Data analysis was carried out using one way ANOVA. ResultsIn all groups, both ΔF (percentage fluorescence loss) and ΔQ (ΔF times the area) values improved significantly within the same group after the treatment. In addition, the mean difference in ΔF of the non-fluoride control group was significantly lower than all other groups but not for the 2800ppm F− group. Whereas the mean difference in ΔQ of the non-fluoride control of group was significantly lower when compared with all other groups (p<0.05). ConclusionsBoth MI Paste and MI Paste Plus when used in conjunction with 1450ppm F did not show a significant increase in efficacy for the remineralisation of bovine enamel subsurface lesions in the model used in this study. Clinical significanceNewer preventive agents such as MI paste and MI paste plus are advocated as promoting remineralisation when used in addition to routine oral care. This in vitro study shows that they may have a limited value in promoting remineralisation over and above that of 1450ppm F toothpaste used twice a day.

Development of long-circulating docetaxel loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles: Optimization, pharmacokinetic, cytotoxicity and in vivo assessments

Long-circulating nanoparticles (NPs) are promising drug delivery vehicles which target solid tumors via enhanced permeation and retention effect. Plackett–Burman (PBD) and Box–Behnken (BBD) designs were adopted to study the effects of factors viz. polymer concentration, surfactant concentration, homogenizer speed, homogenization time and ultrasonication time on responses. A graphical and numerical optimization technique was used to obtain predicted value of the response. The drug entrapment efficiency was approximately 39±0.85%. The particle size of the nanoparticles was found to be 260±2.85nm, while the zeta potential was −18±2.12mV, indicating more stable particles. SEM, TEM, and AFM were used for characterization of surface morphology and the physicochemical characters of NPs. A pharmacokinetic evaluation carried out intravenous administration in healthy Charles Foster rats displayed enhanced systemic bioavailability and plasma drug concentration. The in vivo-in silico assessment by GastroPlus™ showed good prediction accuracy and presented best-fit model. Nanoparticles were also studied for stability testing and were found to be stable concerning their drug content and physical characters. In vitro cytotoxicity was assessed using MCF-7 for percentage inhibition of human breast cancer cell line. Anticancer studies of optimized NPs showed a significant increase in efficacy as observed by relative tumor volume up to 30 days.

Aerosol administration increases the efficacy of oseltamivir for the treatment of mice infected with influenza viruses

Oseltamivir is an influenza neuraminidase inhibitor that along with supportive therapy has shown to help critically ill patients infected with H7N9 and H1N1pdm influenza virus strains to recover from disease. The standard of care recommends the administration of oseltamivir via oral route which represents difficulties in patients with gastrointestinal complications. Here we tested the use of aerosol administration of oseltamivir to treat mice infected with influenza A/H7N9 virus or influenza A/H1N1pdm virus and directly compared this approach to the standard of care, oral administration. Using nose only delivery of aerosolized oseltamivir we observed a significant increase in efficacy of the treatment compared to oral administration characterized by reduced body weight loss, increased survival rate and dose sparing. The preclinical data presented here supports the possibility of using this approach in clinical settings.