Quality of case management of sexually transmitted diseases: comparison of the methods for assessing the performance of providers

Amiodarone is a widely used antiarrhythmic agent with highly variable therapeutic effects. These seem to be related, at least in part, to the pharmacokinetics of the drug and particularly to some features of its gastrointestinal absorption process. The drug exhibits physico-chemical properties highly suitable for diffusion across lipophilic absorbing membranes, but its low aqueous solubility can act as the rate limiting step for absorption, making the process erratic and variable. In order to gain an insight into the intestinal absorption mechanism of the drug and detect possible non-linearities, a series of experiments using a classical rat gut in situ preparation were carried out with three amiodarone hydrochloride solutions (10, 75, and 200 micrograms mL-1). A synthetic non-ionic surfactant, polysorbate 80, at supramicellar concentration (2 mM) was used as the drug solubilizer. Amiodarone was assayed in biological samples by HPLC using a rapid, sensitive technique that was validated. The amiodarone first-order absorption rate constants obtained in these conditions were similar. No significant differences between ka values were found. Amiodarone absorption was clearly identified as a passive diffusion process.     

Treatment of arterial femoropopliteal obstructions with Palmaz midsize stents]

We evaluated the dose-dependent (saturable) gastrointestinal absorption of cefatrizine, an aminocephalosporin transported by peptide carriers, in rats by a physiological mechanism-based approach to clarify its absorption characteristics and to examine the in vitro (in situ)-in vivo correlation in intestinal transport. With an increase in oral dose (mumol/5 ml/kg) from 5 (low) to 50 (high), the intestinal absorption rate constant (ka), which was estimated by analysis of gastrointestinal disposition, decreased markedly, from 0.301 to 0.056 min-1. This decrease was ascribable to the saturability of intestinal membrane transport, of which the concentration dependency in the perfused intestine was similar in extent to the dose dependency in ka. However, the apparent absorption rate constant (ka'), which was estimated by analysis of plasma concentrations after oral administration, decreased only modestly from 0.037 to 0.023 min-1. This was associated with the result that, at the low dose, ka' was far smaller than ka and comparable with k(g) (gastric emptying rate constant), suggesting gastric emptying-limited absorption. At the high dose, where intestinal cefatrizine absorption was less efficient, ka' was closer to ka than k(g). It was also observed that the bioavailability was close to unity, independent of dose, suggesting that the intestinal transit time is long enough to achieve complete absorption, even at the high dose, where intestinal cefatrizine absorption is less efficient. Thus, it was found that the effect of saturability in the intestinal transport of cefatrizine is apparently attenuated in its overall gastrointestinal absorption because of the involvement of gastric emptying and intestinal transit time as additional physiological factors to define absorption. It was also found that a scaling factor is required to correlate the intestinal membrane transport between in vitro (in situ) and in vivo, though this remains to be verified to be utilized for developing oral drug delivery strategies and optimizing oral drug therapy.     

Critical analysis of "flip-flop" phenomenon in two-compartment pharmacokinetic model

Computer simulations were used to examine the effect of first-order absorption on the disposition of one- and two-compartment model drugs. Two-compartment systems that attain a clinically acceptable beta-phase after rapid intravenous injection were perturbed by introduction of drug via first-order absorption. The validity of perceiving such a system as a potential "flip-flop" model was tested by comparing the negative slopes of log-linear plasma-time profiles to known values for ka and beta for various values of ka, k12, k21, and k10. Although most log-linear plots showed excellent correlation coefficients (r2 greater than 0.996), their negative slopes (S) did not represent either ka or beta under various combinations. A similar consideration of the one-compartment model enabled a comparison to be made between the two systems. Maximum negative errors were observed for both one- and two-compartment drugs as ka leads to k2 or beta, respectively. The value for S provided a good estimate of the absorption rate constant, ka, when k2 greater than or equal 2ka (one compartment) or beta greater than or equal 2ka. The elimination rate constant (k2 or beta) could be obtained from S for all one-compartment and some two-compartment drugs when the value of ka was approximately twice that of k2 or beta. Large positive errors also were observed with certain two-compartment drugs where the ratio of the four rate constants apparently linearized a nonlinear plasma profile. Conditions wherein S may be expected to approach beta wherein S approaches ka are clearly defined.     

Simultaneous Removal of Naphthalene and Sulfur Dioxide using Surfactant

Anionic surfactant was added during absorption to investigate the solubility of vapor phase naphthalene and SO2 in water. Anionic surfactant employed was sodium dodecyl sulfate. Lower than critical micelle concentration (CMC), the apparent solubility and absorption rates of SO2 or naphthalene with or without SO2 were practically identical to those of pure water. However, higher than CMC, equilibrium SO2 or naphthalene apparent solubility increased linearly in proportion to the surfactant concentrations. The solubilization effect of micelles resulted in the increase. Because the micelle solubilization effect was greater than that of the decrease of the mass transfer coefficient, the gas absorption rate increased. When surfactant concentration was 0.1 M, the enrichment factor (EF) value of naphthalene with SO2 was 4.54, which was only half of its value without SO2. When surfactant concentration was 0.2 M, the SO2 EF values increased to 2.24. These empirical findings confirm that to increase the removal efficiency of simultaneous absorption of hydrophobic organic compounds and SO2 via a spray or packed tower, an anionic surfactant can be employed.     

The inhibitory effect of carboxymethylcellulose with high viscosity on lipid absorption in broiler chickens coincides with reduced bile salt concentration and raised microbial numbers in the small intestine

Two diets, with or without a nonfermentable carboxymethylcellulose (CMC) with high viscosity, were fed to broiler chickens beginning at 2 wk of age to study whether the anti-nutritive effect of gelling fibers on lipid digestibility may be associated with reduced intestinal bile salt concentration. Moreover, the microflora were examined to study whether possible changes in bile salt concentration coincide with alterations in microbial numbers. Carboxymethylcellulose depressed apparent lipid digestibility (P = 0.021). Feed intake and weight gain were not significantly affected. Water intake was increased in birds fed the CMC diet (P = 0.039). Bile acid concentration in small intestinal digesta was decreased (P = 0.047) in birds fed the CMC diet, which may have been caused by the increased water content of digesta (P < 0.001). The concentration of bile acids per gram dry matter or per milligram chromium was not reduced in small intestinal contents. Broiler chickens fed the CMC diet excreted more bile acids in the excreta (P < 0.001). Total aerobic and anaerobic microbial counts in the intestinal digesta were significantly increased in the duodenum plus jejunum (P = 0.038) but not in the ileum. Significant increases were found in the numbers of Clostridia (P = 0.017), Lactobacillus (P = 0.009), Bacteroides (P = 0.022), and yeasts and molds (P = 0.012). The present study supports the hypothesis that a nonfermentable gelling fiber (CMC) decreases apparent lipid digestibility by reducing the concentration of bile acids in the chyme in broiler chickens. Moreover, the ingestion of gelling fibers may increase the bacterial activity in the small intestine, which may further contribute to malabsorption of lipids.     

Purification of the stress protein alpha B-crystallin and its differentially phosphorylated forms

The subsolubilizing alterations caused by a series of alkyl glucosides (alkyl chain lengths ranging from C8 to C12) in unilamellar phosphatidylcholine (PC) liposomes were investigated. The surfactant to phospholipid molar ratios (RE) and the normalized bilayer/aqueous phase partition coefficients (K) were determined by monitoring the increase of the fluorescence intensity of liposome suspensions due to the 5(6)-carboxyfluorescein (CF) released from the interior of vesicles to the bulk aqueous phase. Given that the free surfactant concentrations was always lower than the critical micelle concentration (CMC) of the surfactant tested we may assume that the surfactant-liposome interactions were mainly ruled by the action of surfactant monomers. In general terms, the decrease in the surfactant alkyl chain length (or the rise in the surfactant CMC) resulted in an increase in the ability of these surfactants to alter the permeability of liposomes and, inversely, in an abrupt decrease in their affinity with these bilayers structures. The overall balance of these opposite tendencies shows that at the two interaction levels studied (50 and 100% of CF release) the nonyl and the octyl glucoside showed, respectively, the highest ability to alter the release of the CF trapped in bilayers (lowest RE values), whereas the dodecyl glucoside showed the highest degree of partitioning into liposomes or affinity with these bilayer structures (highest K values).     

Effects of Surfactants and Temperature on PCP Biodegradation

The effects of temperature and surfactant concentration on the degradation of pentachlorophenol (PCP) by a pure culture of Sphingomonas chlorophenolicum sp. Strain RA2 were studied. An anionic, a cationic, and two nonionic surfactants were tested at concentrations above and below their critical micellar concentrations (CMC). Each surfactant was tested at four temperatures between 10 and 25°C. PCP degradation curves were modeled based on Monod growth kinetics. Degradation curves were also fit using inhibition models accounting for the effects of temperature and surfactant concentration. No PCP degradation activity was observed in the presence of the cationic surfactant. The anionic surfactant had a more inhibitory effect at lower concentrations than the nonionic surfactants, which occurred at surfactant concentrations well below the CMC at all temperatures. Nonionic surfactants showed no inhibition at sub-CMC concentrations and higher temperatures. In general, the surfactants caused more inhibition at lower temperatures. The exception was a slight enhancement of PCP degradation at 10°C for low concentrations of the nonionic surfactants.     

Comparison of the DNA association kinetics of the Lac repressor tetramer, its dimeric mutant LacIadi, and the native dimeric Gal repressor

The rates of association of the tetrameric Lac repressor (LacI), dimeric LacIadi (a deletion mutant of LacI), and the native dimeric Gal repressor (GalR) to DNA restriction fragments containing a single specific site were investigated using a quench-flow DNase I "footprinting" technique. The dimeric proteins, LacIadi and GalR, and tetrameric LacI possess one and two DNA binding sites, respectively. The nanomolar protein concentrations used in these studies ensured that the state of oligomerization of each protein was predominantly either dimeric or tetrameric, respectively. The bimolecular association rate constants (ka) determined for the LacI tetramer exceed those of the dimeric proteins. The values of ka obtained for LacI, LacIadi, and GalR display different dependences on [KCl]. For LacIadi and GalR, they diminish as [KCl] increases from 25 mM to 200 mM, approaching rates predicted for three-dimensional diffusion. In contrast, the ka values determined for the tetrameric LacI remain constant up to 300 mM [KCl], the highest salt concentration that could be investigated by quench-flow footprinting. The enhanced rate of association of the tetramer relative to the dimeric proteins can be modeled by enhanced "sliding" (Berg, O. G., Winter, R. B., and von Hippel, P. H. (1981) Biochemistry 20, 6929-6948) of the LacI tetramer relative to the LacIadi dimer or a combination of enhanced sliding and the superimposition of "direct transfer" mediated by the bidentate DNA interactions of the tetramer.     

Amino acid requirements of the nucleocapsid protein of HIV-1 for increasing catalytic activity of a Ki-ras ribozyme in vitro

The nucleocapsid protein NCp7 of HIV-1 is a single-stranded nucleic acid binding protein with several functions such as specific recognition, dimerization and packaging of viral RNA, tRNA annealing to viral RNA and protection against nucleases. Since some of these functions involve annealing and double-stranded RNA-melting activity we applied the nucleocapsid protein to a hammerhead ribozyme specific for the activated Ki-ras mRNA in vitro, which carries at its mutated codon 12 a GUU site. A synthetic ribozyme containing 2'-O-allyl-modified nucleotides and alternatively in vitro transcribed ribozymes were used. At a one to one molar ratio of substrate to ribozyme almost no cleavage is observed at 37 degrees C. Presence of a synthetic nucleocapsid protein significantly increases the catalytic activity of the ribozyme. Kinetic analyses by means of single and multiple turnover reactions performed at various substrate to ribozyme ratios lead to only a slight stimulation of the rate constants for single turnover reactions. The rate constants in multiple turnover reactions, however, are stimulated up to 17-fold by the presence of the nucleocapsid protein. The activating region of the nucleocapsid protein was characterized by a number of mutants. The mutants demonstrate that activation requires both basic amino acid clusters as evidenced by point mutations. Deletion mutants indicate that the second zinc finger is totally dispensable and that replacement of the first zinc finger by a glycine-glycine spacer only slightly reduces the enhancing effect of the nucleocapsid protein on the ribozyme.     

Synthesis and characterization of N-octanoyl-beta-D-glucosylamine, a new surfactant for membrane studies

The new nonionic glycosidic surfactant N-octanoyl-beta-D-glucosylamine (NOGA, molar mass 305.37 g) was synthesized through an easy and efficient two-step procedure. Specifically, beta-D-glucosylamine was obtained by the replacement of the anomeric hydroxyl of D-glucose by an amino group which was then selectively acylated. NOGA was finally purified by silica gel column chromatography and recrystallization. This compound is stable and soluble in water and usual buffers up to 80 mM at 4 degrees C and up to 0.2 M at 37 degrees C. NOGA solutions are also characterized by a low ultraviolet light absorbance above 250 nm (epsilon 280 approximately 1.5 M-1 cm-1). Due to its very high critical micelle concentration (CMC = 80 mM, as determined by spectrofluorimetry), this surfactant may easily be removed from samples by dialysis or, to a lesser extent, by adsorption onto hydrophobic beads. Furthermore, NOGA is colorimetrically titrable by the ninhydrin method and its weak interference in protein determination by the bicinchoninic acid method is easy to overcome. This surfactant exhibits a good solubilizing power toward membrane proteins, with a marked selectivity for spiralin, a bacterial surface antigen. Protein extraction started below the CMC, but was much more effective above this concentration threshold. NADH oxidase activity, ligand binding by the glycine betaine-binding protein, and antigenicity of more than 20 membrane or soluble proteins were not altered by NOGA. Thus, owing to its extraction efficacy and mildness toward protein structure and activity, NOGA should prove useful for membrane studies and offers the additional advantage of being easy to synthesize at low cost.     

Substituent effect on the oxidation of phenols and aromatic amines by horseradish peroxidase compound I

A stopped-flow kinetic study shows that the reduction rate of horseradish peroxidase compound I by phenols and aromatic amines is greatly dependent upon the substituent effect on the benzene ring. Morever it has been possible to relate the reduction rate constants of monosubstituted substrates by a linear free-energy relationship (Hammett equation). The correlation of log (rate constants) with sigma values (Hammett equation) and the absence of correlation with sigma+ values (Okamoto-Brown equation) can be explained by a mechanism of aromatic substrate oxidations, in which the substrate gives an electron to the enzyme compound I and simultaneously loses a proton. The analogy which has been made with oxidation potentials of phenols or anilines strengthens the view that the reaction is only dependent on the relative ease of oxidation of the substrate. The rate constant obtained for p-aminophenol indicates that a value of 2.3 X 10(8) M-1 S-1 probably approaches the diffusion-controlled limit for a bimolecular reaction involving compound I and an aromatic substrate.     

Structural maintenance of chromosomes protein C-terminal domains bind preferentially to DNA with secondary structure

Structural maintenance of chromosomes (SMC) proteins interact with DNA in chromosome condensation, sister chromatid cohesion, DNA recombination, and gene dosage compensation. How individual SMC proteins and their functional domains bind DNA has not been described. We demonstrate the ability of the C-terminal domains of Saccharomyces cerevisiae SMC1 and SMC2 proteins, representing two major subfamilies with different functions, to bind DNA in an ATP-independent manner. Three levels of DNA binding specificity were observed: 1) a >100-fold preference for double-stranded versus single-stranded DNA; 2) a high affinity for DNA fragments able to form secondary structures and for synthetic cruciform DNA molecules; and 3) a strong preference for AT-rich DNA fragments of particular types. These include fragments from the scaffold-associated regions, and an alternating poly(dA-dT)-poly(dT-dA) synthetic polymer, as opposed to a variety of other polymers. Reannealing of complementary DNA strands is also promoted primarily by the C-terminal domains. Consistent with their in vitro DNA binding activity, we show that overexpression of the SMC C termini increases plasmid loss without altering viability or cell cycle progression.     

An analysis of the effects of retinoic acid and other retinoids on the development of adrenergic cells from the avian neural crest

In the present work, we have investigated the role of all-trans-retinoic acid (all-trans RA), and several other natural and synthetic retinoids, in the development of adrenergic cells in quail neural crest cultures. Dose response studies using all-trans RA and 13-cis RA revealed a dose-dependent increase in the number of adrenergic cells in neural crest cultures. Similar dose response studies using RA isomers and other natural retinoids did not result in the same increases. In order to determine the receptor mediating the effects of all-trans RA in the neural crest, we tested several synthetic analogs which specifically bind to a particular RA receptor (RAR) subtype. We found that the compound AM 580, which activates the RAR-alpha, produced an increase in adrenergic cells similar to that seen with all-trans RA. The compound TTNPB, which activates all RAR subtypes, also resulted in an increase in adrenergic cells. We conclude that the increase in adrenergic cells seen with all-trans RA is mediated by RAR-alpha and possibly RAR-beta. To further define the actions of all-trans RA on the neural crest we incubated cultures with 5-bromo-2'-deoxyuridine (BrdU) to determine whether all-trans RA could affect the rate of proliferation. The results show that while all-trans RA did not increase the fraction of cells incorporating BrdU into their nuclei at early time points (24 h), it did increase BrdU incorporation by tyrosine hydroxylase (TH) positive cells at 5 days in culture. These findings demonstrate that the increase in adrenergic cells seen with all-trans RA in neural crest cultures is likely due to an increase in the proliferation of cells already expressing TH.     

In the search for new anticancer drugs. 29. A study on the correlation of lipophilicities, ionization constants and anticancer activities of aminoxyl labeled TEPA congeners

Ionization constants for a series of sterically hindered pyrrolidine, pyrroline and piperidine derivatives were determined by potentiometric titrations. The pKa values for the secondary amines as a group ranged from about 7.7 to 11.7, whereby the ring size had no decisive effect on the values. The corresponding hydroxylamine derivatives as a group had distinctly lower pKa values than the amine derivatives ranging between about 4.0 and 6.3. It was shown using the Henderson-Hasselbalch equation that at physiological pH, arbitrarily chosen 6, 7 and 8, the amine derivatives would exist mainly in the protonated form, whereas the hydroxylamine derivatives would be expected to be mainly in the unprotonated form. In contrast, the 4-hydroxy-2,2,6,6-tetramethylpiperdin-1-oxyl radical, under analogous conditions, was a neutral species, i.e. it could not be titrated in aqueous media. On the basis of these results, it was hypothesized that the alkylating anticancer drugs of TEPA (N,N:N'N':N",N"-tri-1,2-ethanediylphosphorictriamide) type, containing sterically hindered carrier moieties, would be expected to permeate across cell membranes, and, consequently, exhibit anticancer activities according to the following sequence: spin-labeled drugs containing no titratable components > hydroxylamine derivatives > secondary amine congeners. This assumption is confirmed by good correlations of anticancer activities of these drugs with their pKa values, and the partition coefficients. The conclusion was reiterated that, in the quest for a rational design of anticancer drugs, the aim should be to construct agents with partition coefficients approaching the logarithm of zero, either from the negative or positive side, and pKa values as low as practically possible and applicable.     

Estimation of oral drug absorption in man based on intestine permeability in rats

Predicting the fraction of an oral dose absorbed in humans is of considerable interest at an early stage of a research program in the pharmaceutical industry. Models described in the literature to predict the oral absorption in man include: the permeability in Caco-2 cells, absorption from a perfused segment of rat intestinal lumen and uptake into everted rings. The present study used an isolated and vascularly perfused rat small intestine to determine the permeability values of eleven compounds across the intestinal epithelium. A good correlation was obtained between the permeability values determined in this model and the proportion of an oral dose absorbed in humans. Compared to the other models, the present one could allow the appearance in the artificial bloodstream and the intestinal metabolism of a compound to be studied simultaneously.     

Posteroventral medial pallidotomy in levodopa-unresponsive parkinsonism

PURPOSE: The purpose of this study was to test whether structural modifications improve the intestinal absorption of DMP 728 (cyclo(D-Abu-NMeArg-Gly-Asp-Amb)), a GPIIb/IIIa receptor antagonist. METHODS: In vitro permeabilities of prodrugs and analogs of DMP 728 across excised rat intestinal segments were determined. RESULTS: n-Butyl and n-octyl esters of DMP 728 were relatively stable during in vitro permeation of rat intestine. Intestinal permeation rates of these compounds were no greater than that of DMP 728, even though the octyl ester was much more lipophilic. A pivaloyloxymethyl ester, which was hydrolyzed to DMP 728 during intestinal permeation, also did not improve permeability. In another approach, analogs with an additional methyl substituent on various amide nitrogens were evaluated. Cyclo(D-Val-NMeArg-Gly-Asp-NMeAmb), cyclo(D-Abu-diN-MeLys-Gly-Asp-Amb), and cyclo(NMeGly-NMeArg-Gly-Asp-Amb) each had about 2-fold greater permeability than DMP 728. Two other analogs with improved permeability were linear Ac-D-Abu-NMeArg-Gly-Asp-Amb and a DMP 728 derivative in which the Asp was rearranged. An analog in which the charged amino acids were replaced by neutral amino acids had permeability similar to DMP 728. CONCLUSIONS: Within this series of peptides, hydrogen bonding tendency and structural constraint influenced intestinal permeation, but not always in ways consistent with the literature, whereas charge and lipophilicity were not shown to influence intestinal permeability. The failure of these approaches to improve permeation more significantly could be due to the influence of secretory transport.     

Synthesis, lipophilicity and biological properties of some novel 1H-1,2,4 triazole derivatives

A series of new 1H-1,2,4-triazole derivatives was synthesized and evaluated as potential antiviral (i.e. anti-influenza virus), antibacterial and antifungal agents. The lipophilicity of the compounds was also investigated using calculation procedures. Among the test compounds none showed specific activity against influenza virus, although compound 3a, the most hydrophilic member of the series, showed weak activity against Bacillus subtillis.     

Characterization of the radical trapping activity of a novel series of cyclic nitrone spin traps

alpha-Phenyl-tert-butyl nitrone (PBN) is a nitrone spin trap, which has shown efficacy in animal models of oxidative stress, including stroke, aging, sepsis, and myocardial ischemia/reperfusion injury. We have prepared a series of novel cyclic variants of PBN and evaluated them for radical trapping activity in vitro. Specifically, their ability to inhibit iron-induced lipid peroxidation in liposomes was assessed, as well as superoxide anion (O2(-.)) and hydroxyl radical ((.)OH) trapping activity as determined biochemically and using electron spin resonance (ESR) spectroscopy. All cyclic nitrones tested were much more potent as inhibitors of lipid peroxidation than was PBN. The unsubstituted cyclic variant MDL 101,002 was approximately 8-fold more potent than PBN. An analysis of the analogs of MDL 101,002 revealed a direct correlation of activity with lipophilicity. However, lipophilicity does not solely account for the difference between MDL 101,002 and PBN, inasmuch as the calculated octanol/water partition coefficient for MDL 101,002 is 1.01 as compared to 1.23 for PBN. This indicated the cyclic nitrones are inherently more effective radical traps than PBN in a membrane system. The most active compound was a dichloro analog in the seven-membered ring series (MDL 104,342), which had an IC50 of 26 mum, which was 550-fold better than that of PBN. The cyclic nitrones were shown to trap (.)OH with MDL 101,002 being 20 25 times more active than PBN as assessed using 2-deoxyribose and p-nitrosodimethylaniline as substrates, respectively. Trapping of (.)OH by MDL 101,002 was also examined by using ESR spectroscopy. When Fenton's reagent was used, the (.)OH adduct of MDL 101,002 yielded a six-line spectrum with hyperfine coupling constants distinct from that of PBN. Importantly, the half-life of the adduct was nearly 5 min, while that of PBN is less than 1 min at physiologic pH. MDL 101,002 also trapped the O2(-.) radical to yield a six-line spectrum with coupling constants very distinct from that of the (.)OH adduct. In mice, the cyclic nitrones ameliorated the damaging effects of oxidative stress induced by ferrous iron injection into brain tissue. Similar protection was not afforded by the lipid peroxidation inhibitor U74006F, thus implicating radical trapping as a unique feature in the prevention of cell injury. Together, the in vivo activity, the stability of the nitroxide adducts, and the ability to distinguish between trapping of (.)OH and O2(-.) suggest the cyclic nitrones to be ideal reagents for the study of oxidative cell injury.     

Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position

As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.     

Lyme disease--on the basis of our observations

We biologically assessed functions of several reconstituted surfactants with the same minimum surface tension (2-3 mN/m) as "complete" porcine pulmonary surfactant (natural surfactant) but with longer surface adsorption times. Administration of natural surfactant (adsorption time 0.29 s) into the lungs of surfactant-deficient immature rabbits brought a tidal volume of 16.1 +/- 4.4 (SD) ml/kg during mechanical ventilation with 40 breaths/min and 20 cmH2O insufflation pressure. In static pressure-volume recordings, these animals showed a lung volume of 62.4 +/- 9.7 ml/kg at 30 cmH2O airway pressure and maintained 55% of this volume when the pressure decreased to 5 cmH2O. With two reconstituted surfactants consisting of synthetic lipids or isolated lipids from porcine lungs plus surfactant-associated hydrophobic proteins (adsorption times 0.57 and 0.78 s, respectively), tidal volumes were < 38% of that with natural surfactant (P < 0.05), but static pressure-volume recordings were not different. Care is therefore needed in estimating the in vivo function of surfactant preparations from minimum surface tension or static pressure-volume measurements.