Quantitative correspondence between the in vivo and in vitro activity of teratogenic agents.

We have tested 74 teratogenic and 28 nonteratogenic agents in a recently developed in vitro teratogen assay system. The assay identifies teratogens by their ability to inhibit attachment of ascites tumor cells to plastic surfaces coated with concanavalin A. There is a qualitative agreement between in vivo animal data and in vitro activity for 81 of the 102 agents (79%). Quantitative analysis shows a highly significant correlation coefficient of 0.69 between the inhibitory in vitro dose and the lowest reported teratogenic dose for 54 of the 60 inhibitory teratogens. The doses analyzed ranged over 5 orders of magnitude. We interpret these results to mean that attachment inhibition in concert with other, complementary, in vitro assay systems can become a useful method for the assessment of the teratogenic potential of environmental agents.     

The inhibitory effect of new diphosphonic acids on aortic and kidney calcification in vivo

Three new diphosphonic acids, i.e. compounds containing a P-C-P bond, have been investigated for their ability to inhibit the vitamin D-induced calcification of aortas and kidneys in rats. The compounds were applied orally in various doses.

All of the compounds, which had previously been shown to effectively inhibit the in vitro crystallization of apatite, markedly decreased the amount of calcium deposited in aortas and kidneys. One of the new compounds was substantially more effective than ethane-l-hydroxy-1,1-diphosphonic acid (EHDP), which was used as a reference compound.

Diphosphonic acids might be used therapeutically in man against soft tissue calcification.     

Plasma and synovial fluid gentisate in patients receiving salicylate therapy

Our study was undertaken to assay gentisate, an oxidation metabolite of salicylate, in plasma and synovial fluid (SF) samples from patients taking antiinflammatory doses of aspirin. A close correlation between plasma and SF concentrations was found for (1) salicylate, (2) salicylurate, and (3) gentisate, in 20 patients studied. Our data suggest ready equilibration of these compounds between the plasma and synovial spaces. In vitro experiments confirmed that in the presence of an oxy radical flux, salicylate is oxidized to gentisate. However, no evidence was obtained to implicate peripheral conversion of salicylate to gentisate in inflamed joints where oxy radicals may be produced.     

Utility of animal models for identification of potential therapeutics for rheumatoid arthritis

Animal models of rheumatoid arthritis (RA) are widely used for testing potential new therapies for RA. However, the question of which animal model is most predictive of therapeutic efficacy in human RA commonly arises in data evaluation. A retrospective review of the animal models used to evaluate approved, pending RA therapies, and compounds that were discontinued during phase II or III clinical trials found that the three most commonly used models were adjuvant-induced arthritis (AIA) in rats and collagen-induced arthritis (CIA) in rats and mice. Limited data were found for more recently developed genetically modified animal models. Examination of the efficacy of various compounds in these animal models revealed that a compound's therapeutic efficacy, rather than prophylactic efficacy, in AIA and CIA models was more predictive of clinical efficacy in human RA than data from either model alone.     

Relationship between the duration of the preoperative smoke-free period and the incidence of postoperative pulmonary complications after pulmonary surgery

STUDY OBJECTIVE: To examine the relationship between the duration of the preoperative smoke-free period and the development of postoperative pulmonary complications (PPCs) in patients who underwent pulmonary surgery, and the optimal timing of quitting smoking. DESIGN: Retrospective cohort study. SETTING: Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan. PATIENTS: Two hundred eighty-eight consecutive patients who underwent pulmonary surgery between January 1997 and December 1998. Measurements and results: We collected information on the preoperative characteristics, intraoperative conditions, and occurrence of PPCs by reviewing the medical records. Study subjects were classified into four groups based on their smoking status. A current smoker was defined as one who smoked within 2 weeks prior to the operation. Recent smokers and ex-smokers were defined as those whose duration of abstinence from smoking was 2 to 4 weeks and > 4 weeks prior to the operation, respectively. A never-smoker was defined as one who had never smoked. The incidence of PPCs among the current smokers and recent smokers was 43.6% and 53.8%, respectively, and each was higher than that in the never-smokers (23.9%; p < 0.05). The moving average of the incidence of PPCs gradually decreased in patients whose smoke-free period was 5 to 8 weeks or longer. After controlling for sex, age, results of pulmonary function tests, and duration of surgery, the odds ratios for PPCs developing in current smokers, recent smokers, and ex-smokers in comparison with never-smokers were 2.09 (95% confidence interval [CI], 0.83 to 5.25), 2.44 (95% CI, 0.67 to 8.89), and 1.03 (95% CI, 0.47 to 2.26), respectively. CONCLUSIONS: These findings indicate that preoperative smoking abstinence of at least 4 weeks is necessary for patients who undergo pulmonary surgery, to reduce the incidence of PPCs.     

Does laparoscopic hepatectomy offer benefits for patients with COPD? A propensity score analysis

BackgroundTo date, it remains unclear whether laparoscopic hepatectomy (LH) is safe and feasible for patients with chronic obstructive pulmonary disease (COPD). Thus, we compared the perioperative outcomes of LH versus open hepatectomy (OH) in this special cohort of patients.MethodsBetween February 2014 and October 2020, 162 patients who underwent hepatectomy met the inclusion and exclusion criteria of this study. Perioperative data were compared between the two groups by propensity score matching (PSM) analysis.ResultsAfter PSM, 55 patients with well-balanced baseline data were included in each group. Intraoperative blood loss, overall postoperative complications, and postoperative pulmonary complications (PPCs) were significantly lower in the LH group than in the OH group (P < 0.001, P = 0.047, and P = 0.020 after PSM, respectively). However, major complications, early readmission, and early mortality were comparable between the two groups. According to multivariate analysis, high stage of COPD, preoperative tobacco use, and long operative time were independent risk factors for PPCs, whereas treatment with LH was a protective factor.ConclusionLH is safe and feasible for selected patients with COPD when performed by experienced surgeons, and it has superior perioperative outcomes (especially regarding PPCs) when compared to OH.     

Pain intensity and postoperative pulmonary complications among the elderly after abdominal surgery

OBJECTIVE: The purpose of this study was to determine whether postoperative pain intensity differs between elderly abdominal surgery patients in whom postoperative pulmonary complications (PPC) develop and those in whom they do not. METHODS: The exploratory secondary analysis of data from a prospective study of risk factors for PPC had a convenience sample of 86 patients (> or =60 years old) after abdominal surgery at 3 Midwestern hospitals. Daily measurements from postoperative day (POD) 1 to 6 included: pain (rated 0 to 10) at rest, with coughing, deep breathing, movement and walking, and frequency of ambulation. RESULTS: Sixteen subjects (18.6%) had a PPC develop. Subjects with PPCs had higher mean pain intensities on all measures on each POD than those without. Those with PPCs had significantly higher pain intensities at rest on POD4 (P = .010), with deep breathing on POD2 (P = .015), POD4 (P = .009), POD5 (P = .006), and POD6 (P = .009), were up to a chair significantly fewer times on POD2 (P = .043), and walked significantly fewer times on POD5 (P = .002) and POD6 (P = .000) than those without PPCs. Length of stay for those with PPCs (mean, 17.9 days; standard deviation, 15.9 days; median, 10.0 days) was significantly longer than for those without PPCs (mean, 8.5 days; standard deviation, 4.8 days; median, 7.0 days; P = .000). CONCLUSION: Results provide support for viewing pain as a factor that contributes to the development of PPCs among the elderly population after abdominal surgery. Therefore, nursing interventions of pain assessment and management, deep breathing, and ambulation may influence the incidence of this outcome.     

Unchanged thyrotropin and prolactin responses to thyrotropin releasing hormone after indomethacin treatment.

Experimental effects of prostaglandin synthetase inhibitors have been considered in the literature as a clue to the possible interactions of prostaglandins with the hypothalamic releasing hormones at the pituitary level. Some results of the administration to man of these drugs are apparently in contrast with the in vivo and in vitro animal data. The present investigation deals with the comparison between the thyrotropin releasing hormone (TRH) effect on prolactin and thyrotropin when the hormone was administered intravenously at doses of 50, 100 and 200 microgram respectively to three groups of six men (aged 22 to 30 years), before and on the sixth day of indomethacin administration (50 mg orally at 6-hour intervals). No significant change in the releasing hormone effect was observed either in the case of prolactin, where TRH caused a consistently similar release of the hormone at every dose employed, or in the case of thyrotropin, where a dose-dependent releasing effect was obtained before and after indomethacin treatment.     

Does short-term cessation of smoking before lung resections reduce the risk of complications?

BackgroundSmoking cessation is a highly important preparation before thoracic surgery. We examined the effects of short-term smoking cessation intervention before pulmonary resection on postoperative pulmonary complications (PPCs).MethodsA retrospective analysis of prospectively collected data was performed for 753 patients who underwent curative surgical resection for thoracic malignancy at 3 institutions. Patients with a smoking history were instructed to quit smoking. After confirming smoking cessation by at least four weeks before surgery, surgical resection was performed. Subjects were classified into three groups based on their smoking status: abstainers (anyone who had stopped smoking for at least 4 weeks but less than 2 months), former smokers (anyone who had abstained from smoking for more than two months prior to surgery), and never smokers (those who had never smoked). We examined the relationship between the preoperative smoking status and PPCs.ResultsSurgery was performed for 660 primary lung cancers and 93 metastatic lung tumors. The smoking statuses were classified as follows: abstainers (n=105, 14%), former smokers (n=361; 48%) and never smokers (n=287, 38%). The incidence of PPCs among abstainers, former smokers and never smokers was 15%, 8% and 6%, respectively (P=0.01). The mean duration of post-operative chest tube drainage among abstainers, former smokers and never smokers was 3.2, 2.2 and 2.2 days, respectively (P=0.04). The mean post-operative hospital stay among abstainers, former smokers and never smokers was 12.1, 10.6 and 10.2 days, respectively (P=0.07). There was no 30-day mortality in the cohort.ConclusionsShort-term smoking cessation intervention did not enough reduce the PPCs as much as in former or never smokers.     

Experimental infection with Streptococcus pneumoniae in mice: correlation of in vitro activity and pharmacokinetic parameters with in vivo effect for 14 cephalosporins

A mouse model using intraperitoneal inoculation of Streptococcus pneumoniae type 3 was used to compare in vitro and in vivo effects of 14 cephalosporins, selected to encompass a wide range of minimal inhibitory concentrations (MICs) against the organism. Antibiotics were subcutaneously administered as single doses 1 hr after inoculation of pneumococci, and the effect was measured as the 50% effective dose (ED50). The correlation between log ED50 and log MIC was highly significant (r = .87, P less than .001). Pharmacokinetic properties of the cephalosporins were estimated after a fixed dose of 5 mg per mouse (167 mg/kg) for all drugs. The only correlation that was significant was between log ED50 and the time the serum concentration remained above the MIC for each drug (r = -.90, P less than .001). Ceftriaxone was the most-effective cephalosporin in vivo because of a combination of high in vitro activity and prolonged serum elimination half-life.     

不同吸入氧浓度对行腹腔镜下结肠癌根治术老年病人术后肺部并发症的影响

目的 探讨30％吸入氧浓度(FiO2)与80％FiO2对择期行腹腔镜下结肠癌根治术的老年病人术后肺部并发症(PPCs)的影响.方法 选择择期行腹腔镜下结肠癌根治术的病人120例,美国麻醉医师协会分级为Ⅰ～Ⅱ级,年龄65～80岁,预计手术时间＞1h.将病人随机分为2组:30％ FiO2组(L组)和80％ FiO2组(H组...     

The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam

Here, we show that the synaptic vesicle protein SV2A is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa. Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated LEV derivative, indicating that SV2A is necessary for LEV binding. LEV and related compounds bind to SV2A expressed in fibroblasts, indicating that SV2A is sufficient for LEV binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that SV2A is the binding site of LEV in the brain and that LEV acts by modulating the function of SV2A, supporting previous indications that LEV possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies.     

Comparison of Argatroban and Hirudin for the Reperfusion of Thrombotic Arterial Occlusion by Tissue Plasminogen Activator

Despite theoretical advantages of direct thrombin inhibitors, recent clinical studies failed to show the superiority of hirudin over heparin in patients with acute coronary syndromes. However, these inhibitors have important in vitro differences for the inhibition of clot-bound thrombin that may translate into different in vivo relative efficacy. The effects of two direct thrombin inhibitors, argatroban and hirudin, on the reperfusion of thrombotic arterial occlusion by t-PA were compared. In anesthetized rabbits thrombotic occlusion was induced in the femoral artery. t-PA, aspirin, and various doses of argatroban (1.25, 2.5, and 5.0 mg/kg/h) or hirudin (2.5 and 5.0 mg/kg/h) were administered (six animals in each group). Blood flow was measured for 4 hours. Animals treated with 2.5 mg argatroban more rapidly achieved full reperfusion than those treated with high-dose argatroban or hirudin (P < 0.05). At the doses that induced comparable prolongation of bleeding time, argatroban showed a significantly faster and higher level of reperfusion than hirudin. In animals treated with hirudin, there was a positive correlation between the aPTT and the mean reperfusion blood flow (r = 0.70, P < 0.05). In animals treated with argatroban, this correlation did not exist and the high-dose argatroban was paradoxically less effective in promoting thrombolysis despite greater anticoagulation effects. In this animal model of arterial thrombosis, argatroban was more effective than hirudin in inducing rapid, full reperfusion with t-PA. Although they are both direct thrombin inhibitors, these two agents showed important dose-related differences in efficacy and anticoagulant effects.     

Antitumor activity of clomiphene analogs in vitro: relationship to affinity for the estrogen receptor and another high affinity antiestrogen-binding site

The antitumor activity of three enclomiphene (trans-1- (p-beta-diethylaminoethoxyphenyl)1,2-diphenyl-2-chloroethylene) analogs and the cis isomer zuclomiphene was investigated in MCF 7 human mammary carcinoma cells in culture. Relative antitumor activity was compared with relative binding affinities (RBAs) for the nuclear estrogen receptor (RE; estradiol = 100%) and a microsomal antiestrogen-binding site (AEBS; tamoxifen = 100%) measured in cell-free extracts from MCF 7 cells. Modifications in the structure of the diethylaminoethoxy side chain influenced affinity of both RE and AEBS. Deethylation of the side chain (9599) reduced affinity for both sites by 65-70%, while a diethylaminoproproxy side chain (6866) resulted in a 3-fold increase in affinity for RE (enclomiphene = 2%; 6866 = 6%), but reduced the RBA for AEBS by 66% (enclomiphene = 140%; 6866 = 45%). Conversion of the ether linkage to an amine (10222) increased affinity for RE (10222 = 5%), but markedly reduced affinity for the AEBS (10222 = 15%). All five compounds inhibited the growth of MCF 7 cells in culture, but with markedly different potencies. At low doses (0.25-1.0 microM), where the growth-inhibitory effects were reversed by estradiol (except in the case of zuclomiphene), the relative antitumor activity (6866 greater than 10222 greater than enclomiphene greater than 9599 greater than zuclomiphene) was in the same order as RBA for RE. At higher doses (greater than 2.5 microM), where the growth-inhibitory effects were unaffected or partially reversed by estradiol, the relative potencies of these compounds as antitumor agents changed. Zuclomiphene became the most active, while the potency of enclomiphene increased relative to 6866 and 10222 (zuclomiphene greater than enclomiphene greater than 6866 greater than 10222 greater than 9599). At these doses, estrogen-irreversible antitumor activity was unrelated to affinity for RE, but showed some correlation with affinity for AEBS. It is concluded that the major effect of these compounds on mammary carcinoma growth in vitro is an estrogen-reversible growth-inhibitory effect, the magnitude of which is correlated with affinity for RE. However, studies with zuclomiphene and estrogen-irreversible doses of enclomiphene and 6866 indicate that these antiestrogens also influence cell proliferation in vitro by mechanisms that probably do not involve RE.     

Endoscopic ultrasound-guided drainage of peripancreatic fluid collections: What impacts treatment duration?

Background: Peripancreatic fluid collections(PFCs) are complications resulting from acute or chronic pancreatitis and require treatment in certain clinical conditions. The present study aimed to identify the factors influencing the duration of endoscopic ultrasound(EUS)-guided drainage of symptomatic pancreatic pseudocysts(PPCs), walled-off necrosis(WON), and acute necrotic collections(ANCs). Methods: This was a retrospective cohort study of 68 patients with PFCs who underwent EUS-guided drainag...     

Cholesterol lowering and bile acid excretion in the hamster with cholestyramine treatment.

Cholestyramine was administered to hamsters at 6 doses in the diet for 1 week. Plasma cholesterol, LDL + VLDL cholesterol and HDL cholesterol were measured after this period. Bile acid excretion was measured in faeces collected over the final 24 h of the experiment. A dose-response curve for each parameter measured was constructed using data from individual hamsters. For the bile acid and the cholesterol measurements a maximum response was observed at the highest doses. A correlation between the bile acids excreted over 24 h and the LDL + VLDL cholesterol showed that the maximum effect of cholestyramine on lowering plasma and lipoprotein cholesterol occurred at a submaximal excretion level of bile acids. Comparison of the efficiency of cholestyramine in reducing plasma cholesterol in the hamster with limited data in the dog and in man suggest that a greater lowering of plasma cholesterol is achieved in the dog and in man for an equivalent increase in bile acid excretion caused by the sequestrant. As is already known, cholestyramine treatment caused an increase in hepatic cholesterol 7 alpha-hydroxylase and HMG-CoA reductase activity. Interestingly in this study the novel observation was made that the bile acid sequestrant reduced the activity of hepatic acyl-CoA: cholesterol acyltransferase.     

Physician Practice Patterns and Variation in the Delivery of Preventive Services

Background Strategies to improve preventive services delivery (PSD) have yielded modest effects. A multidimensional approach that examines distinctive configurations of physician attributes, practice processes, and contextual factors may be informative in understanding delivery of this important form of care. Objective We identified naturally occurring configurations of physician practice characteristics (PPCs) and assessed their association with PSD, including variation within configurations. Design Cross-sectional study. Participants One hundred thirty-eight family physicians in 84 community practices and 4,046 outpatient visits. Measurements Physician knowledge, attitudes, use of tools and staff, and practice patterns were assessed by ethnographic and survey methods. PSD was assessed using direct observation of the visit and medical record review. Cluster analysis identified unique configurations of PPCs. A priori hypotheses of the configurations likely to perform the best on PSD were tested using a multilevel random effects model. Results Six distinct PPC configurations were identified. Although PSD significantly differed across configurations, mean differences between configurations with the lowest and highest PSD were small (i.e., 3.4, 7.7, and 10.8 points for health behavior counseling, screening, and immunizations, respectively, on a 100-point scale). Hypotheses were not confirmed. Considerable variation of PSD rates within configurations was observed. Conclusions Similar rates of PSD can be attained through diverse physician practice configurations. Significant within-configuration variation may reflect dynamic interactions between PPCs as well as between these characteristics and the contexts in which physicians function. Striving for a single ideal configuration may be less valuable for improving PSD than understanding and leveraging existing characteristics within primary care practices.     

Biotransformation and pharmacokinetic overview of enoximone and its sulfoxide metabolite

Enoximone possesses both positive inotropic and vasodilatory activities and may be useful in the treatment of patients with congestive heart failure (CHF). In all animal species investigated (rat, dog, monkey and man), the major urinary metabolite is the sulfide oxidation product (sulfoxide); very little unchanged drug appears in urine. Both in vitro and in vivo animal studies indicate reversibility of the sulfoxidation reaction; therefore, it is presumed that sulfoxidation is reversible in man. In normal healthy subjects, no difference in extent of absorption due to dietary state is observed. In patients with New York Heart Association class III to IV CHF, median terminal disposition half-lives for enoximone and its sulfoxide metabolite are 6.2 to 7.6 hours, respectively. Enoximone and sulfoxide plasma concentrations from high dose intravenous infusion studies in atients with class III to IV CHF were also investigated. The collective data suggest nonlinearity in one or more pharmacokinetic processes, of which one may be saturation of sulfoxidation. No direct relation between enoximone and/or the sulfoxide metabolite plasma concentration and pharmacologic effect has been established.