Anti-malarial efficacy of pyronaridine and artesunate in combination in vitro and in vivo

Pyronaridine is a Mannich base anti-malarial with demonstrated efficacy against drug resistant Plasmodium falciparum, P. vivax, P. ovale and P. malariae. However, resistance to pyronaridine can develop quickly when it is used alone but can be considerably delayed when it is administered with artesunate in rodent malaria models. The aim of this study was to evaluate the efficacy of pyronaridine in combination with artesunate against P. falciparum in vitro and in rodent malaria models in vivo to support its clinical application. Pyronaridine showed consistently high levels of in vitro activity against a panel of six P. falciparum drug-sensitive and resistant strains (Geometric Mean IC50=2.24 nM, 95% CI=1.20-3.27). In vitro interactions between pyronaridine and artesunate showed a slight antagonistic trend, but in vivo compared to pyronaridine and artesunate administered alone, the 3:1 ratio of the combination, reduced the ED90 of artesunate by approximately 15.6-fold in a pyronaridine-resistant P. berghei line and by approximately 200-fold in an artesunate-resistant line of P. berghei. Complete cure rates were achieved with doses of the combination above or equal to 8 mg/kg per day against P. chabaudi AS. These results indicate that the combination had an enhanced effect over monotherapy and lower daily doses of artesunate could be used to obtain a curative effect. The data suggest that the combination of pyronaridine and artesunate should have potential in areas of multi-drug resistant malaria.     

我国高血压防治现状和策略

<正>我国现患高血压2亿人,由于人群高血压患病率的不断升高和防控力度不够,我国高血压人群的知晓率、治疗率、控制率仍处于较低水平。对于像高血压这样的群体性慢性病,应当采取全人     

Cooperation of B- and T-lymphocytes of the human in vitro and in vivo

It is reported on the experimental proofs for the existence of a cooperation of different populations of lymphocytes in man. Regulatory lymphocytes play a part in the regulation of the synthesis of immunoglobulins by polyclonally stimulated B-lymphocytes, in the generation of killer-T-cells and in the regulation of the DNA-synthesis by mitogenically stimulated T- and B-cells. Typical helper- and suppressor-effects may be proved. Disturbances of lymphocytic interactions may be a cause for the development of immune deficiency diseases. It is very probable that also in several chronic infections a dysfunction of regulatory T-lymphocytes is present.     

Modulation of enterotoxin binding and function in vitro and in vivo

The use of the nontoxic B subunits of cholera and Escherichia coli enterotoxins in vitro and in vivo led to a decrease in toxin binding to target cells and a decrease in toxin-induced effects (i.e., morphological effects, adenylate cyclase activation, and fluid secretion). The reduction in toxin binding involves a process of down-regulation of cellular receptors for the toxin and not toxin occupancy of receptors. The extent of inhibition was dependent on the amount of B subunit used and on the duration of time after its use. Thus, in vivo exposure to a single bolus of B subunit was sufficient to block toxin binding and activity for up to 18 h. Because the B subunit binds extensively to the esophagus and the stomach, peroral administration will require a preparation that allows the subunit to reach the small bowel in a protected form. Our data provide a rationale for using B subunit therapy for short-term protection against the effects of enterotoxins, before the development of an immune response.     

Uptake of labeled alloxan in mouse organs and mitochondria in vivo and in vitro

[14C]2-Alloxan was administered in vivo and in vitro for study of the uptake of alloxan in different organs and their mitochondia of mice. After in vivo administration, radioactivity was demonstrated in all organs investigated, with quantitative differences: endocrine pancreas greater than liver greater than exocrine pancreas and heart. No significant difference was found between the iv and ip routes of injection. An in vivo uptake of alloxan was also found in mitochondria, with significant quantitative differences as to the origin of the organelles: endocrine pancreas greater than liver greater than exocrine pancreas and heart. Pretreatment with D-glucose caused significantly decreased uptake in liver, exocrine pancreas, and heart, but significantly increased uptake in endocrine pancreas, whereas the uptake was significantly decreased in the mitochondria from all of these organs. In vitro uptake was observed in all kinds of mitochondria studied. This uptake was higher than the in vivo uptake in mitochondria from liver, exocrine pancreas, and heart, whereas the uptake in vivo was higher than the in vitro uptake in islet mitochondria. The presence of D-glucose did not affect the in vitro uptake of alloxan in mitochondria. The findings show that in vivo, alloxan passes across plasma membranes and is taken up by mitochondria, and data obtained with mitochondrial subfractions may also indicate a passage across mitochondrial membranes. D-Glucose protection against alloxan diabetogenicity may be associated with prevention of mitochondrial uptake of alloxan. This prevention seems to be dependent on the metabolism of glucose.     

Patterns of compartment involvement in tibiofemoral osteoarthritis in men and women and in whites and African Americans

Objective

We conducted a cross‐sectional study to describe the prevalence of tibiofemoral joint space narrowing (JSN) in medial and lateral compartments and assess whether it differs by sex and ethnic groups, and, if it does, to what extent such a difference is accounted for by knee malalignment.

Methods

The Multicenter Osteoarthritis Study is an observational study of persons ages 50–79 years with either symptomatic knee osteoarthritis or high risk of disease. Knee radiographs were assessed for JSN in each tibiofemoral compartment. Mechanical axis angle was measured using full‐extremity films. We compared the proportion of knees with medial compartment JSN and with lateral JSN between men and women, as well as between whites and African Americans, using a logistic regression model adjusting for covariates (race or sex and body mass index, age, education, and clinic site). We used generalized estimating equations to account for correlation between 2 knees within a person.

Results

Of 5,202 knees (2,652 subjects), 1,532 (29.5%) had medial JSN and 427 (8.2%) had lateral JSN. Lateral JSN was more prevalent in the knees of women than in men (odds ratio [OR] 1.9, 95% confidence interval [95% CI] 1.5–2.4) and was also higher in the knees of African Americans than in whites (OR 2.4, 95% CI 1.7–3.3). Further adjustment for malalignment attenuated the OR for sex but not the OR for race.

Conclusion

Women and African Americans are more likely to have lateral JSN than men and whites, respectively. Valgus malalignment may contribute to the higher prevalence in women.     

The antibacterial activity of combinations of mecillinam and ampicillin in vitro and in normal and granulopenic mice

The antibacterial activity of mecillinam and ampicillin, alone and in combination, against Escherichia coli was quantitated and compared in vitro and in vivo. Minimum inhibitory concentrations (MICs) were determined for both antibiotics individually and combined. Two-hour growth curves were established in vitro. A quadratic fit to these growth curves provided quantitative concentration-dependent growth characteristics. The antibacterial activity in vivo was determined by applying a short-term thigh muscle infection model to normal and irradiated granulopenic mice. The effects in vivo were also quantitated as dose-dependent or concentration-dependent parameters. Mecillinam showed activity in vitro, but none in vivo. Combinations of mecillinam with ampicillin showed a strong potentiation, as judged from MICs and from short-term experiments in vitro and in the normal and irradiated granulopenic mice. The potentiating activity in vivo was not influenced by host factors (i.e. granulocytes). However, the degree of potentiation indicated by the MICs led to strong overestimation of the effect of the combination of the two antibiotics on short-term in vitro growth. Furthermore, the combined activity in vitro overestimated the potentiating effect of the two antibiotics in vivo.     

Enterobiosis--analysis of infections in human populations of villages and towns and infections in families

The study presents the results of a research on the frequency of infection with Enterobius vermicularis in different urban and rural human populations, conducted by Zoology Department of Podlaska Academy in Siedlce between 1998 and 2006. Since 2001, samples from one examinee were collected seven times. On the basis of the seven tests, a table of the frequency of infection and the efficiency of its detection was presented. The study indicates the populations in which all the infected were detected earlier than after the seventh test. It also presents the results of family infection examination (there were two groups of the examined: A--only children, B--children as well as parents): out of 125 families 47 (37.6%) were infected. The author concluded that the method of taking pinworm samples should be standardized to the Graham method with the samples collected on seven consecutive days, and that whole families should be examined wherever one person is detected to be infected.     

Comparison of in vitro and in vivo rates of collagen synthesis in normal and damaged lung tissue

The rate of collagen synthesis was measured in vivo and in vitro in both normal and damaged mouse lung tissue. Acute lung damage was induced by the administration of butylated hydroxytoluene (BHT). The production of labeled hydroxyproline, following the administration of labeled proline, was used as an index of collagen production. Total and labeled hydroxyproline in normal and damaged lung tissue were solubilized equally following digestion with purified collagenase. Assuming that the extent of hydroxylation was not altered, this indicated that hydroxyproline was an accurate index of collagen content and production in damaged as well as normal lung tissue. The quantities of hydroxyproline formed at various times both in vivo and in vitro were calculated from the specific activity of free proline in lung tissue. The specific activity of free proline in normal and damaged lung tissue remained constant in vivo for at least 90 minutes after the intravenous injection of labeled proline. Hydroxyproline production was a linear function of time for up to 90 minutes in vivo and three hours in vitro. The in vivo rate of hydroxyproline production was significantly greater than the in vitro rate in lung tissue from similarly treated mice. The difference ranged from five-fold in normal lung tissue to eight-fold in lung tissue damaged by the administration of BHT. Comparable differences were seen between the in vivo and in vitro rates of non-collagen protein synthesis. Despite these differences in rates, the percentage of total protein synthesis committed to collagen in vivo was the same as in vitro in normal lung, and identical increases were seen in damaged lung. These data show that in vivo rates of both collagen and non-collagen protein synthesis are significantly higher than those measured in mouse lung tissue in vitro. Although the relative increases in collagen synthesis that occur in response to lung damage are larger in vivo, measurements of collagen synthesis in vitro do accurately reflect the general changes that accompany acute lung damage.     

Mechanism of action and control in the digestion of proteins and peptides in humans

This review aims to report the major control mechanisms of protein and peptides digestion of special interest in human patients. Regarding protein assimilation its digestive process begins at the stomach with some not so indispensable actions comparatively to those of duodenal/jejunal lumen. However even the intestine processes are partially under gastric secretion control. Proteolytic enzyme activities are related to protein structure and amino acid constituents, tertiary and quartenary structures need HCl denaturation prior to enzymatic hydrolysis. Thereafter the exopeptidases are guided by either NH2 (aminopeptidases) or COOH (carboxypeptidases) terminals of the molecule while endopeptidases are oriented by the specific amino acids constituents of the peptide. Both dietary and luminal secreted proteins and polypeptides undergo to either limited or complete proteolysis resulting basic or neutral free-amino acids (40%) or dioctapeptides. The brush border peptidases continue to degrade oligopeptide to di-tripeptides and neutral free-amino acids. Some peptides are uptaked by the enterocytes whose cytosolic peptidases complete the hydrolysis. Hence the digestive products flowing in the portal vein are mainly free-amino acids from either luminal or cytosolic hydrolysis and some di-tripeptides intactly absorbed. Both mechanical and chemical processes of digestion are under neural (vagal), neuroendocrinal (acetilcholine), endocrinal (gastrin, secretin and cholecystokinin) or paracrinal (histamine) controls. The gastric phase (hydrochloric acid and pepsinogen secretions) is activated by gastrin, histamine and acetilcholine which respond to both dietary-amino acids (tryptophan and phenylalanine) and mechanic distention of stomach. The pancreatic secretion is stimulated by either cephalic or gastric phases and has influence on the intestinal phase of digestion. The intestinal types of cells S and I release secretin and cholecystokinin respectively in response of acid quimo (cells S) or amino acids and peptides (cells I) in the lumen. Secretin stimulates the releasing of water, bicarbonate and enteropeptidases whereas cholecystokinin acts on pancreatic enzymes.