Effect of sulfalene and furosemide on benzylpenicillin kinetics in rats with aseptic inflammation

The effect of sulfalen and furosemide on benzylpenicillin kinetics in blood serum, intact tissues and aseptic inflammation foci was studied on rats. It was shown that under the action of sulfalen and furosemide protein binding of benzylpenicillin lowered by 30 per cent. The changes in the antibiotic kinetics after combined use with sulfalen and furosemide were of the same type: markedly increased concentrations in blood serum and tissues and retarded elimination.     

Interactions of sulfanilamides, penicillins and acetylsalicylic acid in serum protein binding

Combined use of sulfalen and sulfadimethoxine with benzylpenicillin and ampicillin resulted in increased binding of sulfalen to serum proteins of man. Acetylsalicylic acid promoted a decrease in the sulfanilamide binding to the serum proteins. The observed changes in the sulfanilamide binding to proteins of human blood serum were due to increased or decreased affinity of the drugs to the protein molecules.     

Characteristics of the distribution of long-acting sulfanilamides in purulent pyelonephritis in rats

Distribution of sulfalen, sulfadimethoxine and sulfamethoxypyridazine in the blood and organs of rats and binding of the drugs to the blood serum proteins of the animals with experimental P. aeruginosa pyelonephritis were studied. It was shown that in rats with P. aeruginosa pyelonephritis the levels of long-acting sulfanilamides in the blood and organs were lower, while the levels of their penetration through the histohematic barriers were higher, which was partially due to the decreased binding of sulfanilamides to blood proteins.     

Effects of sulfalene on the thymus, spleen and adrenals in an experiment]

The effect of sulfalen on the weight and structure of the thymus, spleen and adrenal glands was studied. The findings were compared with the results observed in control rats. It was shown that after administration of sulfalen, the weight of the adrenal glands markedly decreased while their structure did not change. Thymus specimens showed a large number of hypertrophic epitheliocytes, in the medulla which was accompanied by a decrease in its weight.     

Sulfalene pharmacogenetics. I. The genetic determination of the pharmacokinetic indices

Genetic determination of pharmacokinetics of sulfalen, a new antibacterial drug, has been studied in 28 twin pairs of Moscow Russian population. In order to determine the degree of heritability of such pharmacokinetic parameters of sulfalen as t 1/2 (half-life); Vd and delta (apparent and specific volumes of distribution) and Co (apparent initial concentration) Holtsinger H-statistics values have been calculated, which are 0.891, 0.866, 0.766 and 0.797 respectively. Possible causes of discrepancies between these values and the coefficients of genetic determination G, calculated by decomposition of general phenotypical dispercion of the parameters via the main equation of quantitative traits of genetics are given (0.913, 0.762, 0.828, 0.856 in that order). The data obtained make it possible to assume that genetic determination t 1/2 of sulfalen is carried out within the system of monogenous interaction (HD = 0.91, HA = 0), that of Vd and Co--within the system of additive-polygenous interaction, while linear and non-linear effects contribute to delta determination (HD = 0.232, HA = 0.596).     

Sulfalene pharmacogenetics. II. The population genetic aspect

Half-life of sulfalen, a new antibacterial drug, with the biotransformation, performed by means of microsomal acetyltransferase, has been studied in 53 individuals of Moscow Russian population. The absence of sex dimorphism for the trait studied is demonstrated. Distribution of individuals according to values of the pharmacokinetic parameter mentioned within the population is bimodal with the correlation of phenotypic frequencies of "rapid" and "slow" inactivators--72 and 28%. Possible causes of discrepancies between the observed sulfalen inactivator frequencies and similar data on isoniazid are discussed.     

Achievements and problems from the view of a physician

Penicillin made possible the cure of many common, and also the most serious, infections, such as meningococcal meningitis and bacterial endocarditis, often with few or no sequelae. Endocarditis had been invariably fatal. Semisynthetic penicillins added new dimensions of convenience of administration and a broader spectrum in the presence of many beta-lactamases. A quantum step forward was permitted by the derivatives of cephalosporin C. Specific clinical advances were (1) the opportunity to use these in some penicillin-allergic patients, (2) activity against wider range of Gram-negative bacilli, (3) activity against Bacteroides fragilis (cefoxitin), (4) more complete renal excretion after oral cephalosporins than with oral penicillins, and (5) delayed renal excretion. Major remaining problems limiting beta-lactam use are (1) allergy, (2) resistant organisms, (3) relatively poor entry into the cerebrospinal fluid (especially of cephalosporins, (4) some nephrotoxicity, (5) local irritation of veins and tissues during administration, and (6) poor results in patients with agranulocytosis.     

Patterns of clometacillin circulation in the body of laboratory animals]

Distribution of clometacillin in mice, rats and rabbits was studied in comparison with some other penicillins. It was found that clometacillin was superior to all other penicillins used for comparison with respect to the circulation time in the blood after intravenous, intramusclar or intrastomach administration. As for the capacity for penetrating into the tissues from the blood, clometacillin was not inferior to ampicillin and benzylpenicillin and was superior to propicillin, though it was bound by the blood serum proteins to a greater extent than the other penicillins used for comparison.     

Linking organ donors and the medical/scientific research community: a US perspective

The International Institute for the Advancement of Medicine (IIAM) provides non-transplantable organs and tissues for medical and scientific research, education, and drug & device development. The benefits of using human organs and tissues for research are vast, and donating for research provides donor families with a valuable option if their loved one??s organs are unsuitable for transplantation. The use of these organs and tissues enables the faster development of more efficacious drugs with improved safety profiles, and enhanced understanding of basic disease processes that directly affect humans. Human organs and tissues offer unique advantages over the use of animal organs and tissues as it is human diseases and conditions which we seek to treat, and so logically the results can be more directly applied. The added advantage of accessing non-transplantable, human organs is that they are in superb condition, and so experiments can be conducted in a very physiologically-relevant system. Although the US is a sizeable country with a large population and individual regulations governing human tissue collection and usage for each of the 50 states comprising the US this article will discuss how IIAM succeeds in immediately linking organ donors and qualified researchers, ultimately to the great benefit of patients.     

低温对黑线仓鼠能量代谢、抗氧化能力和氧化应激的影响

为探讨低温对机体能量代谢、器官/组织抗氧化能力和过氧化自由基水平的影响及其内在联系,本研究测定了不同时间低温和梯度低温处理的黑线仓鼠的摄食量、体重、主要内脏器官/组织的过氧化物歧化酶（SOD）、过氧化氢酶（CAT）、H₂O₂和丙二醛（MDA）水平。低温使摄食量显著增加,但未影响体重。低温暴露42 d使心脏和骨骼肌MDA水平、骨骼肌SOD活性显著升高;梯度低温使脑和肾脏H₂O₂水平、肝脏和骨骼肌SOD活性显著降低,使脑、肝脏、肺、肾脏MDA水平、脑和小肠SOD活性显著升高。抗氧化能力和过氧化自由基水平在不同器官之间相关性存在差异,同一器官内二者的相关性在肾脏为100%,肝脏66.7%,骨骼肌50.0%。结果表明：（1）过氧化自由基的产生与低温暴露的时间和程度有关;（2）不同器官/组织过氧化自由基水平不同;（3）部分器官/组织抗氧化酶活性的变化与过氧化自由基水平的变化密切相关,可能是防止过氧化损伤的主要防御系统。     

The pathogenesis of radiation injury in complex tissues: an overview of problems and probes

The evaluation of radiation injury in complex organs has tended to lag behind comparable areas of investigative interest. This observation is somewhat surprising in view of the increased use of radiotherapy as a primary or adjuvant mode of therapy for malignant disease. In part, this problem appears to relate to the difficulty of identifying and quantifying the morphologic consequences of radiation injury in complex organs, in which the various component tissues exhibit a broad spectrum of radiosensitivities. Two approaches have been employed to address this problem: (1) utilization of sophisticated probes to evaluate the functional and morphologic sequelae of radiation injury and (2) segmentation of complex tissues into their component parts, which are then evaluated individually. Both approaches are illustrated in the papers presented in this issue. The purpose of this overview is to call attention to some of the attendant difficulties of the former approach, as seen in an ongoing investigative program concerned with radiation injury of the kidney.     

Effects of cold acclimation on the activity levels of creatine kinase, lactate dehydrogenase and lactate dehydrogenase isoenzymes in various tissues of the rat.

The effects of cold acclimation on the activity levels of creatine kinase, lactate dehydrogenase and lactate dehydrogenase isoenzymes in various tissues/ organs of the rat (Rattus norvegicus) were investigated. Male Sprague-Dawley rats were divided into two groups. One group was housed at 4+/-1 degrees C (experimental group) and the other at 24+/-1 degrees C (control group) for six months. The rats were housed in single cages and had access to food and water ad libitum. The tissues/organs investigated were heart, liver, lung, kidney, gastrocnemius muscle and interscapular brown adipose tissue as well as serum. With the exception of lung, (which showed a decrease of 24%) total creatine kinase activity levels were significantly increased (P< 0.05) in all the tissues/organs investigated (17-51%) as well as serum (34%), in cold acclimated animals. Cold acclimation also resulted in significantly increased (P< 0.05) activity levels of lactate dehydrogenase in all the tissues/organs investigated (14-24%) as well as serum (35%). Cold exposure resulted in an increase of the activity levels of all the detectable isoenzymes of lactate dehydrogenase, although not always significant, in all the tissues/organs investigated as well as serum. The M(4)tetramer of lactate dehydrogenase was the only detectable isoenzyme in serum.     

Analysis of multiple bacterial species and antibiotic classes reveals large variation in the association between seasonal antibiotic use and resistance

Understanding how antibiotic use drives resistance is crucial for guiding effective strategies to limit the spread of resistance, but the use–resistance relationship across pathogens and antibiotics remains unclear. We applied sinusoidal models to evaluate the seasonal use–resistance relationship across 3 species (Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae) and 5 antibiotic classes (penicillins, macrolides, quinolones, tetracyclines, and nitrofurans) in Boston, Massachusetts. Outpatient use of all 5 classes and resistance in inpatient and outpatient isolates in 9 of 15 species–antibiotic combinations showed statistically significant amplitudes of seasonality (false discovery rate (FDR) < 0.05). While seasonal peaks in use varied by class, resistance in all 9 species–antibiotic combinations peaked in the winter and spring. The correlations between seasonal use and resistance thus varied widely, with resistance to all antibiotic classes being most positively correlated with use of the winter peaking classes (penicillins and macrolides). These findings challenge the simple model of antibiotic use independently selecting for resistance and suggest that stewardship strategies will not be equally effective across all species and antibiotics. Rather, seasonal selection for resistance across multiple antibiotic classes may be dominated by use of the most highly prescribed antibiotic classes, penicillins and macrolides.

A study of the relationship between antibiotic use and resistance in Boston, Massachusetts shows that antibiotic resistance in multiple pathogens peaks in the winter/spring and is most correlated with the use of penicillins and macrolides – the antibiotics with winter-peaking use.     

Pharmacokinetics of isoniazid and rifampicin in an experiment and in clinical practice

Efficacy of drugs in patients with pulmonary tuberculosis mostly depends on their concentration in organs and tissues. To show distribution profiles of antituberculous drugs in patients in organs and tissues of experimental animals after their administration alone or in combination, pharmacokinetic parameters of isoniazid and rifampicin were studied. The drug concentrations, half-lives and distribution volumes were determined in 50 patients and 60 experimental animals. It was observed that after combined use of isoniazid and rifampicin their concentrations in the lung tissue and liver of the experimental animals increased which led to increasing their half-lives in patients.     

Changes in fatty acid composition of thymus cells, liver, blood plasma, and muscle tissue in mice with solid Ehrlich carcinoma

The fatty acid composition of thymus cells, liver, blood plasma, muscle tissue, and tumor focus has been studied in mice with solid Ehrlich carcinoma. The tumor growth in the mice was associated with an increase in the total content of monounsaturated fatty acids in all organs and tissues studied and with a decrease in the total amount of polyunsaturated fatty acids in all tissues except blood plasma. The tumor tissue was characterized by increased levels of monounsaturated fatty acids in comparison with their levels in organs and tissues of intact animals. In the thymus of tumor-bearing mice, the contents of myristic and palmitic saturated fatty acids, which are associated with activation of the T-cell immunity, were increased. The most expressed and considerable changes in the fatty acid composition during tumor growth were observed in the muscle tissue of the animals. A possible role of changes in the fatty acid composition in the investigated organs and tissues of tumor-bearing mice in the organism’s response to tumor growth is discussed.     

Virtual mutation and directional evolution of anti-amoxicillin ScFv antibody for immunoassay of penicillins in milk

In this study, an anti-amoxicillin single chain variable fragment (ScFv) antibody was evolved by directional mutagenesis of a contact amino acid residue based on the analysis of virtual mutation. Comparison with its parental ScFv, the mutant showed highly improved affinity for 11 penicillins with up to 6-folds increased sensitivity. Then, its recognition mechanisms for the 11 drugs were studied by using molecular docking. Results showed that the mutant-penicillins intermolecular forces increased and the total binding energies decreased dramatically, which were responsible for the improvement of antibody sensitivity. The ScFv mutant was used to develop an indirect competitive enzyme linked immunosorbent assay for determination of the 11 drugs in milk. The limits of detection were in the range of 0.2–3.0 ng/mL, the crossreactivities were in the range of 31%–132%, and the recoveries from standards fortified blank milk were in the range of 65.7%–92.4%. This is the first study reporting the directional evolution of a ScFv antibody based on virtual mutation and the use of ScFv antibody for determination of penicillins in foods of animal origin.     

黑线姬鼠与大林姬鼠组织中超氧化物酶和过氧化物酶的分布与活性比较

以黑线姬鼠(Apodemus agrarius)和大林姬鼠(A. peninsulae)为研究对象,采用聚丙烯酰胺凝胶电泳(PAGE)不连续体系的方法,比较分析了心、肝、肾、肌肉、脑、肺6种器官和组织中超氧化物酶(SOD)和过氧化物酶(POD)活性,并建立了2种酶的电泳图谱。结果显示,上述2种酶在黑线姬鼠和大林姬鼠的6种器官和组织中均有表达并表现出明显的特异性,其中,2种鼠中超氧化物酶共分离出迁移率由0.15～0.66的9条电泳谱带,过氧化物酶共分离出迁移率由0.09～0.83的20条电泳谱带。在肝和肺中酶的活性最强,黑线姬鼠6种器官和组织中超氧化物酶活性均强于大林姬鼠,2种鼠组织中过氧化物酶的活性和分布相似,但在同一物种不同器官和组织间过氧化物酶的活性及分布存在明显差异。     

Lipid peroxides and human diseases

Development of a simple and reliable method to determine the lipid peroxide level in human serum or plasma has made it possible to survey the levels in human diseases. Since in some human diseases lipid peroxides are increased in various organs or tissues and leak into the bloodstream, the increased lipid peroxide level in the blood aids the diagnosis of such diseases. Furthermore, determination of the level provides useful information as to their prognosis, since the increased lipid peroxides in the blood primarily attack the endothelial cells of vessels and then intact organs or tissues as well. The present paper describes a method to determine the lipid peroxide level in human serum or plasma and its profile of change in several human diseases. Intervention of lipid peroxides in the pathogenesis of certain diseases is also mentioned.     

Effect of a hypertonic sodium chloride solution on dye distribution in the organs and lymph of the thoracic duct]

The distribution of trephan blue in different organs and tissues and in the lymph was studied in acute experiments on 84 dogs after the infusion of 5% NaCl solution (0.5 mg/kg). The rise of the stain concentration in the intact dogs was the greatest in the liver, the kidney and the intestine. The osmotic shift caused by the intravenous infusion of the hypertonic NaCl solution increased the blood plasma hyaluronidase activity, reduced the maximal accumulation time of the stain in the tissues and led to a 1.5-2 fold elevation in the stain concentration in the organs.