Major abdominal surgery and the clearance of lipid emulsions

Reaction of bacterial adhesins with complementary receptors on the surfaces of mucosal respiratory, gastrointestinal and genitourinary cells leads to bacterial adhesion to the human body. This is the first step in the sequence of events leading to infection. It has been observed that subinhibitory concentrations (sub-MICs) of some antibiotics are able to reduce bacterial adhesion. The pharmacokinetic curves of antibiotics show that these sub-MICs are present in tissues during a typical course of therapy. This study investigated the ability of sub-MICs of seven macrolides and four fluoroquinolones to reduce adhesiveness of Staphylococcus aureus to human buccal cells. The literature generally reports data for only one antibiotic at a time. To obtain an overall view of the findings of eleven antibiotics together, the data have been normalized according to the molecular weight of each antibiotic and the dose-effect curves determined.     

Serum pharmacology of amphotericin B applied in lipid emulsions

Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.     

Surface composition regulates clearance from plasma and triolein lipolysis of lipid emulsions

Sphingomyelin (SM) and cholesterol (Chol) are major surface lipid constituents of plasma lipoproteins. We investigated the effects of SM and Chol on the plasma clearance of lipid emulsions as a model for lipoprotein particles in rats. The presence of Chol facilitated the removal of emulsion particles from plasma, whereas SM delayed particle removal. Preinjection of lactoferrin, an inhibitor of the apolipoprotein E (apoE) receptor, revealed that the differences in clearance of emulsions were due to the differences in affinity for the apoE receptor. Measurement of apolipoprotein binding suggested that the balance of apoE and apoC (apoC-II and apoC-III) bound to emulsions caused the difference in plasma clearance of emulsion particles. That is to say, SM in the emulsion surface decreased binding of apoE, which led to a longer circulation of emulsion particles in plasma. Chol, on the other hand, decreased the ratio of apoC to apoE, which may have promoted emulsion uptake through the apoE receptor. We also examined in vitro lipolysis using immobilized lipoprotein lipase (LPL) in a heparin affinity column. Lipolysis rates were significantly reduced by the incorporation of SM into the emulsion surface, but not by the incorporation of Chol, indicating that SM in the lipoprotein surface is an important lipid component regulating LPL-mediated lipolysis. Our results suggest that the presence of SM and Chol in the lipoprotein surface plays an important role in the circulation behavior and LPL-mediated lipolysis of lipid emulsions through their effect on the selectivity of plasma protein binding.     

Statistics and comparative pharmacokinetics (author's transl)

An example stresses the point of well established routines, which are usual in comparative pharmacokinetics today. It seems to be necessary to analyse the problem carefully, before starting any pharmacokinetical trial.     

The pharmacokinetics of isoniazid in children (author's transl)

The purpose of this study, which involved 134 children aged between 0.5 and 17 years, was to investigate the metabolism of isoniazid (INH) in children and to provide guide-lines for dosage. The distribution of slow (55,5%) and fast (44,5%) acetylators was the same in children as in adults. However, the mean of INH inactivation index were lower (0.23 and 0.48) while distribution volumes, (1.30 +/- 0.06 and 1.57 +/- 0.17 1/kg) and total plasma clearances (5.39 +/- 0.43 and 14.7 +/- 1.5 ml/Kg/min) were higher than in adults. Plasma half-lives were similar in children and adults. These results indicate that INH is more rapidly metabolized in children owing, it is suggested to a higher liver weight : body weight ratio and to a more pronounced first pass effect. The doses of INH therefore must be higher in children and strictly adapted to each individual.     

Naturally occurring variation in copia expression is due to both element (cis) and host (trans) regulatory variation

Significant differences in levels of copia [Drosophila long terminal repeat (LTR) retrotransposon] expression exist among six species representing the Drosophila melanogaster species complex (D. melanogaster, Drosophila mauritiana, Drosophila simulans, Drosophila sechellia, Drosophila yakuba, and Drosophila erecta) and a more distantly related species (Drosophila willistoni). These differences in expression are correlated with major size variation mapping to putative regulatory regions of the copia 5' LTR and adjacent untranslated leader region (ULR). Sequence analysis indicates that these size variants were derived from a series of regional duplication events. The ability of the copia LTR-ULR size variants to drive expression of a bacterial chloramphenicol acetyltransferase reporter gene was tested in each of the seven species. The results indicate that both element-encoded (cis) and host-genome-encoded (trans) genetic differences are responsible for the variability in copia expression within and between Drosophila species. This finding indicates that models purporting to explain the dynamics and distribution of retrotransposons in natural populations must consider the potential impact of both element-encoded and host-genome-encoded regulatory variation to be valid. We propose that interelement selection among retrotransposons may provide a molecular drive mechanism for the evolution of eukaryotic enhancers which can be subsequently distributed throughout the genome by retrotransposition.     

Interaction of Propagating Radicals with Copper(I) and Copper(II) Species

The effects of copper(I) and copper(II) metal centers on the atom transfer radical polymerization (ATRP) of styrene and methyl acrylate were investigated. The free-radical polymerizations were initiated by AIBN in the presence of copper(I) and copper(II) complexes. For methyl acrylate, the rate of the polymerization was reduced in the presence of CuIBr/dNbpy and CuIOTf/dTbpy but was unaffected by the presence of CuII(OTf)2/dTbpy. For styrene, under conditions which yield relatively low molecular weight polymer (16 000), no effect was observed in the presence of CuII(OTf)2/dNbpy; however, under conditions which yield high molecular weight polystyrene (50 000-100 000), the polymerization was limited in the molecular weight attainable and stopped at partial conversion. No effect was observed for the free-radical polymerization of styrene in the presence of copper(I) complexes. These results indicate that control in ATRP does not originate in interactions of growing radicals with copper complexes but in the reversible halogen atom transfer.     

Diabetes mellitus and lipid metabolism (author''s transl)

Fifteen infants with pneumonia caused by respiratory syncytial virus (RSV) and 19 infants with bronchiolitis caused by RSV were studied for the influence of homologous, circulating neutralizing antibody on the severity of their illness. All infants were under nine months of age. Although maternal neutralizing antibody did not prevent infection with RSV and illness, the severity of pneumonia caused by RSV was inversely related to the level of neutralizing antibody. The severity of bronchiolitis caused by RSV was unrelated to maternal antibody levels. Chest roentgenograms showed pneumonia to be slightly more severe than bronchiolitis. Neither the severity of illness nor the presence of maternal neutralizing antibody was related to the development of complement-fixing antibody.     

Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice

To overcome the low oral bioavailability of the highly potent and selective antiretroviral agent (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), a new lipophilic ester derivative, i.e., the bis(isopropyloxycarbonyloxymethyl)-ester [bis(POC)-PMPA], was prepared. The usefulness of bis(POC)-PMPA as an oral prodrug for PMPA was investigated in the intestinal mucosa Caco-2 cell monolayer model. The total transport of bis(POC)-PMPA was 2.7%, whereas it was less than 0.1% for PMPA. Bis(POC)-PMPA was considerably metabolized inside the epithelial cells, since the majority of the compound was recovered after transport in the form of the monoester metabolite [mono(POC)-PMPA]. In contrast, bis(POC)-PMPA was relatively resistant to degradation at the luminal side of the Caco-2 cells. Pharmacokinetic studies with mice showed that the oral bioavailability of bis(POC)-PMPA (calculated from the curves of the concentration of free PMPA in plasma) was 20%. Neither bis(POC)-PMPA nor mono(POC)-PMPA could be recovered in plasma, suggesting the efficient release of the active drug PMPA after oral administration of bis(POC)-PMPA. Severe combined immunodeficient (SCID) mice infected with Moloney murine sarcoma virus (MSV) and treated orally with bis(POC)-PMPA for 5 or 10 days (dosages, 50, 100, or 200 mg of PMPA equivalent per kg of body weight per day) showed a significant delay in MSV-induced tumor appearance and tumor-associated death. The antiviral efficacy of oral bis(POC)-PMPA was related to the dosage and treatment period and was not significantly different from that of subcutaneous PMPA given at an equivalent dose. The favorable pharmacokinetic profile, marked antiviral efficacy, and low toxicity make bis(POC)-PMPA an attractive oral prodrug of PMPA that should be further pursued in clinical studies with patients infected with human immunodeficiency virus or hepatitis B virus.     

Cranial allometry and geographic variation in slow lorises (Nycticebus)

A series of 20 craniodental measurements was obtained for two sister taxa: Nycticebus coucang (common slow loris) and N. pygmaeus (pygmy slow loris). Multivariate analysis of variance was performed with adult data to describe patterns of subspecific and specific variation in this genus. The geometric mean of adult cranial dimensions was compared to field data on latitudinal coordinates for available specimens to investigate if size variation in Nycticebus is clinal in nature. Ontogenetic series for larger-bodied N. coucang and smaller-bodied N. pygmaeus were compared to test the hypothesis that species and subspecific variation in skull form results from the differential extension of common patterns of relative growth. A MANOVA provides independent support of Groves's [pp. 44-53 in Proceedings of the Third International Congress on Primatology, Vol. 1 (Basel: S. Karger), in 1971)] classification of Nycticebus into two species, with four subspecies in the common slow loris and one form of the pygmy slow loris. Within N. coucang, cranial proportions for all four subspecies are ontogenetically scaled, and size differentiation is mainly clinal (Bergmann's Rule). N. c. bengalensis represents the most northerly disposed and the largest form. N. c. javanicus represents the next-largest form and is located in a southerly direction the next-farthest away from the equator. N. c. coucang and N. c. menagensis are both equatorial; however, the latter subspecies is the smallest. A genetic basis for some of the taxonomic variation between N. c. coucang and N. c. menagensis is supported by such nonclinal variation in body size. Variation in the presence/absence of I2 is not size-related but rather tracks geographic proximity and isolating factors which predate the most recent inundation of the Sunda Shelf. Although they inhabit a nonequatorial environment, pygmy slow lorises are the smallest of all Nycticebus. As N. pygmaeus is sympatric with N. c. bengalensis, the largest slow loris, it appears that the evolution of its smaller body size represents a case of character displacement. Unlike N. coucang, skull size becomes significantly smaller in more northern N. pygmaeus. This may also reflect character displacement between sympatric sister taxa underlain by a cline-dependent ecological factor which is marked in more northerly latitudes. On the other hand, the negative correlation between body size and latitude in N. pygmaeus could be due to the influence of nonprimate fauna, such as predators, which themselves evince a similar clinal pattern. Analyses of relative growth indicate that skull proportions in the two species of Nycticebus are ontogenetically scaled in two-thirds of the cases. All but one of the seven comparisons (interorbital breadth) which do not indicate ontogenetic scaling represent part of the masticatory complex. This likely reflects a reorganization of N. pygmaeus maxillomandibular proportions linked to smaller size and changes in diet.     

Stereoselective metabolism, pharmacokinetics and biliary elimination of phenylethylhydantoin (Nirvanol) in the dog

The influence of stereoisomerism on pharmacokinetics and rates of hepatic drug metabolism was investigated in four dogs using the enantiomers of phenylethylhydantoin (PEH) as model substances. After single i.v. administration of 98 micromoles of the pure enantiomers per kg b.wt., concentrations were measured by gas-liquid chromatography. The l-form exhibited a longer plasma half-life (23.3 +/- S.E. 1.0 hour) than the d-form (16.3 +/- 1.0 hour, P less than .005). Volumes of distribution and renal clearances were practically identical. The differences in plasma half-lives of PEH were explained by stereoselectivity of hepatic hydroxylation: an approximately 10-fold differences was found in urinary excretion of their major metabolities, d- and l-hydroxyphenylethylhydantoin (HPEH). Furthermore, in bile 7.3 +/- 1.6 mumol of of d-HPEH were eliminated within the first 6 hours, whereas l-HPEH could not be detected. The preference in biliary output of d- compared with l-PEH is consistent with the idea that both hepatic uptake and microsomal hydroxylation of PEH contribute to the high degree of stereoselectivity. In view of similar extrahepatic, but different metabolic behavior of these enantiomers, they represent an interesting research tool for in vivo studies of drug metabolism: in otherwise identical conditions, two different rates of PEH hydroxylation may be studied.     

Prenatal and postpartum pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) and didanosine (dideoxyinosine) in pigtailed macaques (Macaca nemestrina)

Stavudine (5 mg/kg of body weight; n = 7) or didanosine (3.2 mg/kg; n = 4) was administered as an intravenous bolus to pregnant pigtailed macaques (Macaca nemestrina) near term and 4 to 5 weeks postpartum. No significant differences were found between the prenatal and postpartum total plasma drug clearance, steady-state volume of distribution, terminal plasma drug half-life, mean body residence time, or recovery of unchanged drug in urine. These data indicate that pregnancy does not affect the pharmacokinetics of stavudine or didanosine in M. nemestrina.     

Contingent negative variation (CNV) and psychological processes in man.

Discusses contingent negative variation (CNV), a slow, surface-negative electrical brain wave occurring in the interval between the presentation of a warning stimulus and an imperative stimulus to which a motor response is usually required. CNV appears as a negative shift in the EEG base line that averages approximately 20 MUV. A 2-process theoretical model is proposed to account for CNV results: magnitude of CNV is positively and monotonically related to attention and nonmonotonically (inverted U) related to arousal level. CNV is also associated with other kinds of electrophysiological activity, notably autonomic functions and slow cerebral potentials that accompany voluntary motor movements. Although CNV is clearly a cerebral phenomenon, eye movements can seriously distort its measurement. It is concluded that CNV is an electrical phenomenon of the human brain that is related chiefly to attention and arousal functions. (5 p. ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

集团变分法(CVM)的发展与应用

阐述了集团变分法(CVM)配置熵近似的特点.概括介绍了CVM在近年来的发展与应用,包括CVM与相图计算CALPHAD方法相结合描述多元系中的短程和长程有序;CVM的配置熵与第一性原理的形成焓计算相结合评估相平衡;CVM与路径概率方法相结合描述非平衡过程;以及连续位移-CVM处理具有晶格畸变或热振动体系的相稳定性.阐明CVM在计算材料学领域越来越重要的作用.     

Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins

The mdr1-type P-glycoproteins (P-gps) confer multidrug resistance to cancer cells by active extrusion of a wide range of drugs from the cell. To study their physiological roles, we have generated mice genetically deficient in the mdr1b gene [mdr1b (-/-) mice] and in both the mdr1a and mdr1b genes [mdr1a/1b (-/-) mice]. In spite of the host of functions speculatively attributed to the mdrl-type P-gps, we found no physiological abnormalities in either strain. Viability, fertility, and a range of histological, hematological, serum-chemical, and immunological parameters were not abnormal in mdr1a/1b (-/-) mice. The high level of mdrlb P-gp normally present in the pregnant uterus did not protect fetuses from a drug (digoxin) in the bloodstream of the mother, although the protein did reduce drug accumulation in the adrenal gland and ovaries. Pharmacologically, mdr1a/1b (-/-) mice behaved similarly to the previously analyzed mdr1a (-/-) mice, displaying, for instance, increased brain penetration and reduced elimination of digoxin. However, both mdr1a and mdr1b P-gps contributed to the extrusion of rhodamine from hematopoietic progenitor cells, suggesting a potential role for the endogenous mdr1-type P-gps in protection of bone marrow against cytotoxic anticancer drugs. This, and the normal viability of mdr1a/1b (-/-) mice, has implications for the use of P-gp-blocking agents in cancer and other chemotherapy. mdr1a/1b (-/-) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs.     

Sputum and serum pharmacokinetics of loracarbef (LY163892) in patients with chronic bronchial sepsis

BACKGROUND: Carbon dioxide absorption into the blood during laparoscopic surgery using intraperitoneal carbon dioxide insufflation may lead to respiratory acidosis, increased ventilation requirements, and possible serious cardiovascular compromise. The relationship between increased carbon dioxide excretion (VCO2) and intraperitoneal carbon dioxide insufflation pressure has not been well defined. METHODS: In 12 anesthesized pigs instrumented for laparoscopic surgery, intraperitoneal carbon dioxide (n = 6) or helium (n = 6) insufflation pressure was increased in steps, and VCO2 (metabolic cart), dead space, and hemodynamics were measured during constant minute ventilation. RESULTS: VCO2 increases rapidly as intraperitoneal insufflation pressure increases from 0 to 10 mmHg; but from 10 to 25 mmHg, VCO2 does not increase much further. PaCO2 increases continuously as intraperitoneal insufflation pressure increases from 0 to 25 mmHg. Hemodynamic parameters remained stable. CONCLUSIONS: By considering Fick's law of diffusion, the initial increase in VCO2 is likely accounted for by increasing peritoneal surface area exposed during insufflation. The continued increase in PaCO2 without a corresponding increase in VCO2 is accounted for by increasing respiratory dead space.     

Biochemistry and pharmacokinetics of potent non-steroidal cytochrome P450(17alpha) inhibitors

Two potent non-steroidal inhibitors (CB7645 and CB7661) of human cytochrome P450(17alpha) were tested for in vivo activity in WHT mice. There were no signs of toxicity, but there was no effect on the androgen-dependent organs. The pharmacokinetics and biochemistry of the compounds in mice were investigated. Following i.p. administration of 0.5 mmol/kg of CB7645 and CB7661, peak plasma levels of 13.4 and 3.4 microM, respectively, occurred after 2-4 h, both compounds were cleared rapidly (terminal half-lives 2.7 and 3.3 h, respectively) and neither was detectable at 24 h. CB7645 produced some decrease in plasma testosterone at 4 h, but this was not sustained. When tested in vitro against the WHT testicular enzyme, the CB7645 and CB7661 were competitive inhibitors with K(i) values of 10 and 13 nM, respectively. However, the K(m) for the substrate progesterone was lower at 4.3 nM. These data indicate that, for effective and continuous inhibition of the murine cytochrome P450(17alpha) enzyme, higher peak levels of the compounds would be required, and these levels would need to be maintained throughout the treatment period.