Establishment of a database of in vitro combined drug efficacy against multi-drug resistant Gram-negative bacilli / 中华微生物学和免疫学杂志

Objective@#To study the synergistic and additive effects of commonly used antibiotics on multi-drug resistant Gram-negative bacilli and to establish a database of combined pharmacodynamics in vitro.@*Methods@#Seven antibiotics including fosfomycin (PHOS), levofloxacin (LEV), ceftazidime (CAZ), compound sulfamethoxazole (SMZ), piperacillin/tazobactam (TZP), cefoperazone/sulbactam (SCF) and imipenem (IMP) were selected and grouped into 21 drug pairs. Based on the results of extended spectrum β-lactamases (ESBLs) test and modified carbapenem inactivation method (mCIM), a total of 172 strains of multidrug-resistant Gram-negative bacilli were divided into four groups: 20 strains of carbapenem-resistant Klebsiella pneumoniae (group A), 50 strains of pan-resistant Acinetobacter baumannii (group B), 62 strains of ESBLs-producing Enterobacter (group C) and 40 strains of carbapenem-resistant Pseudomonas aeruginosa (group D). Chessboard dilution method was used to detect the in vitro combined efficacy of 21 drug pairs on drug-resistant bacteria from the four groups. Whonet 5.6 was used for statistical analysis.@*Results@#All 172 strains were single drug resistant to the seven antibiotics. Results of the combined drug efficacy test showed that no antagonism was found in the four groups. In group A, ten drug pairs, especially the combination of PHOS+ LEV (30%, 6/20), had synergistic effects and 14 showed partial synergistic effects, but no additive effect was detected. Synergistic effects, partial synergistic effects and additive effects were respectively achieved by 12, ten and three drug pairs in group B. The LEV+ SMZ combination had synergistic effects against 56% (28/50) of the strains, which was the highest among all combinations. There were 14, 17 and 16 drug pairs showing synergistic effects, partial synergistic effects and additive effects in group C, respectively, and the strongest synergistic effects were achieved by the IMP+ LEV combination (30.6%, 19/62). There were 12, 14 and 13 drug pairs having synergistic effects, partial synergistic effects and additive effects in group D, respectively, and the strongest synergistic effects were achieved by the IMP+ LEV combination (20%, 8/40).@*Conclusions@#The combined use of quinolones, carbapenems, sulfonamides and PHOS could have good synergistic effects against multi-drug-resistant gram-negative bacilli. Monitoring the in vitro combined efficacy before treatment would improve the accuracy of antibiotic use and is of great clinical value.

Establishment of a database of in vitro combined drug efficacy against multi-drug resistant Gram-negative bacilli / 中华微生物学和免疫学杂志

Objective To study the synergistic and additive effects of commonly used antibiotics on multi-drug resistant Gram-negative bacilli and to establish a database of combined pharmacodynamics in vitro. Methods Seven antibiotics including fosfomycin (PHOS), levofloxacin (LEV), ceftazidime ( CAZ ) , compound sulfamethoxazole ( SMZ ) , piperacillin/tazobactam ( TZP ) , cefoperazone/sulbactam ( SCF) and imipenem ( IMP) were selected and grouped into 21 drug pairs. Based on the results of extended spectrum β-lactamases ( ESBLs) test and modified carbapenem inactivation method ( mCIM) , a total of 172 strains of multidrug-resistant Gram-negative bacilli were divided into four groups:20 strains of carbapenem-resistant Klebsiella pneumoniae ( group A) , 50 strains of pan-resistant Acinetobacter baumannii ( group B) , 62 strains of ESBLs-producing Enterobacter ( group C) and 40 strains of carbapenem-resistant Pseudomonas aeruginosa ( group D) . Chessboard dilution method was used to detect the in vitro combined efficacy of 21 drug pairs on drug-resistant bacteria from the four groups. Whonet 5. 6 was used for statistical analysis. Re-sults All 172 strains were single drug resistant to the seven antibiotics. Results of the combined drug effi-cacy test showed that no antagonism was found in the four groups. In group A, ten drug pairs, especially the combination of PHOS+LEV (30％, 6/20), had synergistic effects and 14 showed partial synergistic effects,but no additive effect was detected. Synergistic effects, partial synergistic effects and additive effects were respectively achieved by 12, ten and three drug pairs in group B. The LEV+SMZ combination had synergis-tic effects against 56％ (28/50) of the strains, which was the highest among all combinations. There were 14, 17 and 16 drug pairs showing synergistic effects, partial synergistic effects and additive effects in group C, respectively, and the strongest synergistic effects were achieved by the IMP+LEV combination (30. 6％, 19/62). There were 12, 14 and 13 drug pairs having synergistic effects, partial synergistic effects and addi-tive effects in group D, respectively, and the strongest synergistic effects were achieved by the IMP+LEV combination (20％, 8/40). Conclusions The combined use of quinolones, carbapenems, sulfonamides and PHOS could have good synergistic effects against multi-drug-resistant gram-negative bacilli. Monitoring the in vitro combined efficacy before treatment would improve the accuracy of antibiotic use and is of great clinical value.

Scientific Thinking on Key Mode of Action of Chinese Medicine / 世界科学技术-中医药现代化

Scientifically elucidating the mode of action of Chinese medicine has become an urgent challenge to Chinese medicine researchers.Opinions on the mode of Chinese medicine effect are active.The scientific hypothesis that additive effect is the key mode of action for Chinese medicine,trigger the scholars and experts in pharmacology field of Chinese medicine to think and contend.The opinion of additive effect provides a new interpretation for mode of action and action characteristics of Chinese medicine.It plays a positive role in the development of pharmacology of Chinese medicine.According to current research results of traditional Chinese medicine (TCM) and clinical cases,this paper made further thinking and summary on the key mode of action for Chinese medicine.The summary is as follows.The diversity of Chinese medicine structure and complexity of Chinese medicine targets determine the complicated mode of action of Chinese medicine.Mode of action for Chinese medicine is complex and variable,which is to adapt to changes in the environment.The genetic diversity of the body receptors due to evolution and the diversity of Chinese medicine and biological complex network control system have determined that a single component of Chinese medicine is more likely to act synergistically by targeting on different targets.From the point of view of Monarch,Minister,Assistant and Guide theory of Chinese medicine,additive effect has limitation.Therefore,just using additive effect is unable to fully explain the Chinese medicine compatible regularity of Monarch,Minister,Assistant and Guide theory.Additive effect is one of action types for Chinese medicine.It is worth to consider if there has any other more important action type for Chinese medicine.

Establishment of new method for quantitatively calculating synergistic, additive and antagonistic effect in multiple-drug combination / 中国药理学与毒理学杂志

Given the complexity of diseases and etiology of multiple targets and links,therapies with multi-drug combination towards multiple targets are better options for treating serious diseases,such as cancer,than a single-target medicine. Multi-drug combination may cause interactions at different levels,but the efficacy of these drugs manifests itself as synergism,addition or antagonism. Because there is no reliable quantitative method for synergism,addition and antagonism that can simultaneously withstand double test of mathematics and pharmacology,the development of novel drug combinations has come to a standstill. By exchanging the equivalent doses and introducing two basic principles that have been long neglected in the pharmacological field(the sequential principle for multi-drug use and the collective property of efficacy)into the geometrical analysis of the dose- effect relationships,the author has found the mathematical laws for the expected additive effect in multi-target drug combina?tion,and worked out a universal formula. The dose-effect relationship of the expected addition is a number set function of multi-drug combination doses with a closed interval,which performs as a belt in a two- dimensional coordinate,while the actual observed one presents as a curve. The number of curves that constitute the belt increases exponentially whith the incnease of combined drugs. By solv? ing the equation groups composed of the belt and the curve,related parameters in multi-drug combina?tion can be precisely calculated,such as dose ranges of synergism,addition and antagonism,as well as combination indexes based on dose and one based on efficacy,which will also provide a quantita?tive analysis method for interactions between various factors in biological systems.

Effective Forms, Additive Effect, and Toxicities Scattering Effect of Pharmacodynamic Substances of TCMs Some Reflections Evoked by the Study on the Metabolic Disposition of Traditional Chinese Medicines (TCM) / 世界科学技术-中医药现代化

The blood concentrations of the pharmacodynamic substances of traditional Chinese medicines (TCMs) are usually very low. How can they exert pharmacological actions, in which forms (original form, metabolite or the both) do they exert the actions. To answer these questions, we proposed a new concept ofEffective Formsof pharmacodynamic substances of TCMs and a hypothesis of additive effect of multiple constituents of TCMs. The hypothesis includes that the aggregate or summation of Effective Forms of pharmacodynamic substances of TCMs is the core material base of the effi-cacy of TCMs, and the additive effect of the blood concentrations of different Effective Forms is one part of the action mechanism. The additive effect of the different Effective Forms of a TCMs means an additive effect of numerous con-stituents or/and metabolites on a same target, and therefore the efficacy brought by the addition of the concentrations of all these compounds, which different from the synergy effect of multi-constituents on multi-targets. Studies on the disposition of TCMs showed that a constituent can be biotransformed to many metabolites (up to more than 50 metabolites);different constituents can produce the same metabolites;many metabolites (up to 10 compounds for each metabolite) are isomers or homologues; some constituents can be converted to each other in vivo; and some metabolites are bioactive. These com-pounds having the similar structure are likely to have the same pharmacological effects on the same target, which could provide experimental evidences for the concept ofEffective Formsand the hypothesis ofAdditive Effect. We suggest that the Effective Forms and Additive Effects of the pharmacodynamic substances of TCMs should be extensively investi-gated in the future, and the results of such researches will help us further understand the pharmacodynamic substances and action mechanism of TCMs, and give a new explanation 'Toxicities Scattering Effect' for 'Why the toxicities of TCMs are low', and propose a new strategy for quality control of TCMs.

Avaliação do desempenho na pós-desmama para uma população bovina multirracial Aberdeen Angus x Nelore utilizando-se diferentes modelos genéticos / Post weaning performance evaluation for a multibreed Aberdeen Angus x Nellore population using different genetic models

Com o objetivo de testar modelos genéticos alternativos ao aditivo-dominante em populações multirraciais, foram utilizadas informações do peso ao sobreano (PS) de 35.931 novilhos, filhos de 752 touros e 30.535 vacas das raças Aberdeen Angus (A) e Nelore (N) e de diversos grupos genéticos possíveis por meio do cruzamento entre elas. Foram testados cinco diferentes modelos (M) genéticos: o M1 continha o efeito genético fixo aditivo direto (AD), heterozigótico direto (HD), epistático direto (ED) e aditivo-conjunto direto (ACD); o M2, igual ao M1, menos o efeito ACD; o M3, igual ao M1, menos o efeito ED; o M4, igual ao M1, menos os efeitos ED e ACD; e o M5, igual ao M1, menos os efeitos HD, ED e ACD. Os modelos foram submetidos a três métodos de análise diferentes: método dos quadrados mínimos (MQM), regressão de cumeeira (RC) e máxima verossimilhança restrita (REML). O método de RC produziu estimativas de coeficientes com magnitudes e sinais explicados biologicamente. As estimativas dos efeitos, das (co)variâncias, dos parâmetros e dos valores genéticos diferiram entre os modelos, indicando a importância da correta escolha do modelo de análise, devendo-se ter conhecimento prévio do fenômeno estudado e sua interpretação biológica e sempre preceder à escolha de um modelo de análise genética multirracial o estudo da relação existente entre as variáveis independentes. Importantes efeitos adicionais ao efeito AD foram acrescentados pelas inclusões dos efeitos HD e ED aos modelos de análise. A notação matemática dos efeitos ACD, aplicada atualmente na literatura e testada neste estudo, não foi capaz de explicar a complementaridade entre raças como esperado, havendo problemas com casos de multicolinearidade entre os efeitos estudados.

In order to evaluate alternative genetic models to the additive dominant model, weights at yearling (PS) of 35,931 animals, sired by 752 bulls and 30,535 cows of Aberdeen Angus (A) and Nellore (N) breeds and the genetic groups from their crosses were used. Five different genetic models (M) were tested: M1, containing the direct additive fixed genetic effect (DA), heterozygote direct (HD), epystatic direct (ED), and direct joint additive direct (DJA); M2 was equal to M1, excluding DJA effect; M3 was equal to M1, excluding ED effect; M4 was equal M1, excluding ED and ACD effects, and M5 was equal to M1, excluding HD, ED, and DJA effects. The models were analyzed by different methods: Least Square Means Method (MQM), Ridge Regression Method (RC), and Restricted Maximum Likelihood Method (REML). Estimated coefficients by RC showed magnitude and sign which were biologically explained. The estimates of the covariances, parameters, and genetic values varied among the models, indicating the importance of the correct choice of the model for analysis, being necessary a previous knowledge of the studied phenomenon and its biological interpretation. Besides, it should always be considered the relationship between the independent variables before choosing a multibreed genetic analysis model. Important additional effects to the DA effect were considered by the inclusion of the HD and ED effects to the models for analysis. The DJA math notation, currently used in the literature and tested in the present study, was not able to explain the breed complementarity, due to the multi colinearity among the studied effects.

Adjuvant Effect of NSAIDs on the Cytotoxicity of Colon Cancer Cells to 5-FU

PURPOSE: Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, is believed to be an important enzyme related to colorectal cancer. A large number of studies have supported the concept that non-steroidal anti-inflammatory drugs (NSAIDs) targeting COX alter the biologic processes of colon carcinogenesis. Although COX-2 inhibitors generally reduce the growth rate of established tumors, tumor regression is rarely observed. Hence, it is reasonable that COX-2 inhibitors be given in conjunction with standard anti-cancer therapy in treating cancer. We investigated whether aspirin and meloxicam not only are cytotoxic but also potentiate the antitumor effect of 5-Fluorouracil (5-FU) against colon cancer cells. METHODS: Expressions of COX-1 and COX-2 were determined by using the reverse transcriptase-polymerase chain reaction (RT-PCR) & Western blotting assay in 9 colon cancer cell lines. The cytotoxicities of NSAIDs and/or 5-FU were determined by using a microculture tetrazolium dye (MTT) assay. RESULTS: COX-1 mRNA and protein, as well as COX-2 mRNA, were variably expressed in all the cell lines tested whereas COX-2 protein was expressed in HT-29 and to a lesser extent in HCT-8, but not in the other cell lines. We selected two representative cell lines, HT-29 expressing COX-2 protein and SNU-C1 not expressing it. The dose-dependent cytotoxicity was observed in both cell lines treated with aspirin and with meloxicam. A combination treatment of aspirin or meloxicam with 5-FU revealed some additive effect, rather than a synergistic effect, for both cells lines. This additive effect was remarkable even for low concentrations of the drugs. Furthermore, the additive effect was highest when the combination was adminstered sequentially, 5-FU followed by aspirin or meloxicam, in both cell lines. CONCLUSIONS: These results suggest that a combination therapy using NSAIDs and 5-FU might be useful in the treatment of colon cancer cells not expressing COX-2, as well as in colon cancer cells expressing COX-2.

A Study On The Heritability And Interfamilial Variation Of Digital Dermatoglyphic Patterns.

Forty eight random families from the population of Andhra Pradesh were selected for the analysis of digital dermatoglyphic patterns and patterns intensity index (PII). The loops were found to be more frequent in the present sample followed by whorls and arches. Sex difference was not evident in the frequency distribution of digital patterns. There was no significant bilateral assymetry in the distribution of digital patterns between the right and left hands of the individuals. The dermatoglyphic patterns showed a specific trend in their distribution on individual fingers, i.e., whorls occurred frequently on finger IV, ulnar loops on finger V, radial loops on finger II and arches on finger II. The pattern intensity index as calculated from the different digital patterns exhibited high heritability values. The correlation coefficients of pattern intensity index between various familial relationships were found to be significant indicating the involvement of genetic factors, mostly autosomal. The partitioning of total phenotypic variance into various components of variance revealed the action of polygenes with more of additive effect, dominance deviation being negligible. This was confirmed by analysis of variance (ANOVA). In general, our study indicated the involvement of polygenes with additive effect and also of environmental components which might be intra-uterine in origin.