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At least 289 records · Page 16Linked to original sources
PubMed1999

Effect of severity of arm impairment on response to additional physiotherapy early after stroke.

OBJECTIVE: To investigate effect of initial severity of arm impairment on response to additional physiotherapy for the arm after stroke. DESIGN: In this controlled trial, patients were randomized into one of three groups: routine physiotherapy (RPT) patients received no additional physiotherapy; qualified physiotherapy (QPT) patients received additional treatment from a qualified physiotherapist; assistant physiotherapy (APT) patients received additional treatment from a trained supervised assistant. Comparisons between the whole groups found no significant differences and have been reported elsewhere. In a post hoc analysis, the groups were subdivided according to severity of initial arm impairment. The subgroups were then compared. SETTING: A general hospital with acute and rehabilitation facilities for stroke patients. SUBJECTS: Patients (n = 282) between one and five weeks after stroke. INTERVENTIONS: Ten hours additional physiotherapy were given over a five-week period. The treatment approach reflected current usual British practice. 'Blind' outcome assessment was performed after intervention, and at three and six months after stroke. MAIN OUTCOME MEASURES: Rivermead Motor Assessment Arm Scale, Action Research Arm Test. RESULTS: In more severe patients, no benefits of additional treatment were detected. In less severe patients, significant benefits were found in those who completed treatment with the trained assistant. However, a considerable number of patients did not complete the additional treatment. The content of treatment differed between the QPT and APT groups. Treatment of less severe APT patients emphasized repetitive supervised practice of movements and functional tasks. No significant effects of additional treatment were found in terms of shoulder pain or spasticity. CONCLUSIONS: Regardless of whether additional physiotherapy was given or not, patients with severe arm impairment improved very little in arm function. Enabling adaptation to loss of arm function may be an appropriate rehabilitation strategy for some patients. Trends in the data confirm findings of some previous studies that intensive treatment for patients with some motor recovery of the upper limb is effective. Following patient assessment and treatment planning by a qualified physiotherapist, it may be appropriate for guidance of repetitive practice of motor and functional tasks to be delegated to trained and closely supervised assistant staff.

Activities of Daily Living↗
PubMed2005

Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate.

PURPOSE: To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). PATIENTS AND METHODS: Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. RESULTS: Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. CONCLUSION: The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2005

Thyroid-hormone-disrupting chemicals: evidence for dose-dependent additivity or synergism.

Endocrine disruption from environmental contaminants has been linked to a broad spectrum of adverse outcomes. One concern about endocrine-disrupting xenobiotics is the potential for additive or synergistic (i.e., greater-than-additive) effects of mixtures. A short-term dosing model to examine the effects of environmental mixtures on thyroid homeostasis has been developed. Prototypic thyroid-disrupting chemicals (TDCs) such as dioxins, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers have been shown to alter thyroid hormone homeostasis in this model primarily by up-regulating hepatic catabolism of thyroid hormones via at least two mechanisms. Our present effort tested the hypothesis that a mixture of TDCs will affect serum total thyroxine (T4) concentrations in a dose-additive manner. Young female Long-Evans rats were dosed via gavage with 18 different polyhalogenated aromatic hydrocarbons [2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin-like PCBs] for 4 consecutive days. Serum total T4 was measured via radioimmunoassay in samples collected 24 hr after the last dose. Extensive dose-response functions (based on seven to nine doses per chemical) were determined for individual chemicals. A mixture was custom synthesized with the ratio of chemicals based on environmental concentrations. Serial dilutions of this mixture ranged from approximately background levels to 100-fold greater than background human daily intakes. Six serial dilutions of the mixture were tested in the same 4-day assay. Doses of individual chemicals that were associated with a 30% TH decrease from control (ED30), as well as predicted mixture outcomes were calculated using a flexible single-chemical-required method applicable to chemicals with differing dose thresholds and maximum-effect asymptotes. The single-chemical data were modeled without and with the mixture data to determine, respectively, the expected mixture response (the additivity model) and the experimentally observed mixture response (the empirical model). A likelihood-ratio test revealed statistically significant departure from dose additivity. There was no deviation from additivity at the lowest doses of the mixture, but there was a greater-than-additive effect at the three highest mixtures doses. At high doses the additivity model underpredicted the empirical effects by 2- to 3-fold. These are the first results to suggest dose-dependent additivity and synergism in TDCs that may act via different mechanisms in a complex mixture. The results imply that cumulative risk approaches be considered when assessing the risk of exposure to chemical mixtures that contain TDCs.

Animals↗
PubMed2002

Testing non-additivity of biological activity in a combinatorial library.

Combinatorial chemistry offers new opportunities to generate and analyze QSAR data. Traditional QSAR attempts to correlate activity with structure. With combinatorial chemistry, it is possible to correlate activity directly with the reagents used in a combinatorial library. If one can determine which reagents lead to the compounds of highest activities, it may then be possible to predict active compounds in virtual libraries of 10(6) to 10(10) compounds. This would greatly facilitate library design and provide confidence that the best compounds are being considered for synthesis. An important question is whether the activity of a product molecule can be considered as a sum of its components. This is referred to as additivity between reagents. If there is non-additivity, it is necessary to identify and include the non-additive terms in the model in order to improve QSAR models. Presented here are methods for developing QSAR models relating compound activity to reagents and a method for detecting the second effects of side-chain non-additivity. If the reagents in a library are shown to be additive in their contribution to activity, simple QSAR based on additive models can be applied confidently to reagents. Testing non-additivity can also guide the synthesis of the library. If the contributions are shown to be additive then the strategy for library synthesis may be shifted to include many reagents of a given type but not to make all combinations. The result is more efficient use of resources. In the analysis of percent inhibition data of a combinatorial library an additive model using reagents as descriptors yields a R(2) of 0.43. Application of this method is probably appropriate for HTS single point data while methods employing topological or pharmacophore based descriptors would be necessary to adequately model IC50 data.

Combinatorial Chemistry Techniques↗
PubMed1991

Additive and nonadditive genetic variance in female fertility of Holsteins.

Additive and nonadditive genetic variances were estimated for cow fertility of Holsteins. Measures of fertility were first lactation days open and service period as recorded and with upper bounds of 150 and 91 d, respectively. Six million inseminations from the Raleigh, North Carolina Processing Center were used to form fertility records of 379,009 cows. Data were analyzed with a model accounting for all additive, dominance, and additive by additive covariances traced through sires and maternal grandsires. Variance components were estimated by the tilde-hat approximation to REML. Heritability in the narrow sense was 2% for days open and .8% for service period. Dominance and additive by additive variance as a percentage of phenotypic variation strongly depended on imposition of upper bounds. Heritabilities in the broad sense ranged from 2.2 to 6.6% and were at least twice as large as heritabilities in the narrow sense. Effect of 25% inbreeding was only around an additional 3 d open. Specific combining abilities among bulls were estimated as sums of dominance and additive by additive interactions removing effect of inbreeding depression. Differences between maximum and minimum estimates were in the order of twice the estimated standard deviation, ranging from 1.5 to 6.7 d. Effects of inbreeding and specific combining ability could be jointly considered in mating programs following sire selection.

Animals↗
PubMed2006

Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

OBJECTIVES: To determine whether cognitive behavioural therapy (CBT) in addition to antispasmodic treatment offers a cost-effective benefit to primary care patients with irritable bowel syndrome (IBS) and to identify predictors of outcome. DESIGN: This was a randomised controlled trial in primary care of the addition of CBT to standard general practice management of IBS, using the antispasmodic agent mebeverine hydrochloride. The study set out to compare the addition of a standardised package of IBS-specific CBT to treatment with mebeverine hydrochloride. SETTING: Ten general practices, serving a population of around 45,000 patients, located principally in south London, with some patients resident in north London. PARTICIPANTS: Patients identified as having IBS by their GPs, aged between 17 and 54 (mean 34) years and predominantly white; 82% were female and half had had IBS for more than 5 years. INTERVENTIONS: Practice nurses delivered CBT in a randomised trial of the addition of CBT to mebeverine in patients who had IBS of moderate or greater severity after 2 weeks of GP care and 4 weeks of mebeverine. The Symptom Severity Scale (SSS) was used to identify patients with moderate or severe IBS. Patients who continued to report moderate or severe IBS after 4 weeks of mebeverine at a dose of 270 mg three times a day were randomised to receive six sessions of CBT in addition to mebeverine (72 patients) or mebeverine alone (77 patients). These patients were followed at 3, 6 and 12 months after treatment. As part of the baseline evaluation, blood tests for antiendomysial and antigliadin antibodies were carried out on 141 patients to determine the prevalence of coeliac disease in this population. MAIN OUTCOME MEASURES: The principal outcome measure was the SSS. Others included the Hospital Anxiety and Depression Scale, psychopathology, the Work and Social Adjustment Scale (WASA, disability), a modified version of the Illness Perception Questionnaire (illness perceptions), the Beliefs about Medicine Questionnaire (attitudes to medication), the Reported Adherence to Medication Scale (adherence to prescribed medication), the Client Service Receipt Inventory (economic analysis), the Cognitive Scale for Functional Bowel Disorders (illness cognitions) and the Behaviour Scale for IBS (IBS coping behaviour). RESULTS: The addition of CBT produced a significant benefit compared with the mebeverine-only group at 3 months after treatment on all outcome measures, except for the adherence to medication scales. The difference between the groups was 107.8 points on the SSS, 24.5 points on question 4 of the SSS and 6.3 points on the WASA, representing therapeutic gains of approximately 20%, 28% and 40%, respectively. However, there was also evidence that these improvements began to wane, so that at 6 and 12 months follow-up significant therapeutic benefit of the addition of CBT could only be detected on question 4 of the SSS and on the WASA. The behaviour scale for IBS detected significant, positive changes in coping behaviours at up to 6 months after treatment. Three factors predicting a poor outcome were identified: male gender, believing that IBS had serious consequences and belief in an external aetiology, all of which were associated with greater than average disability at follow-up. The addition of CBT to mebeverine did not reduce overall treatment or social costs. The nested study on testing for coeliac disease provides cautious support for the inclusion of antiendomysial and antigliadin antibody testing in the investigation of patients thought to have IBS. CONCLUSIONS: Specially trained practice nurses can provide effective CBT to primary care patients with a clinical diagnosis of IBS, which although effective does not reduce service or social costs. Using a variety of measures the beneficial therapeutic effects of the addition of CBT to antispasmodic therapy persist for up to 6 months. Future research might include studies of the long-term follow-up of IBS patients treated with CBT, cost-benefit analyses comparing CBT with other therapeutic approaches to IBS, and evaluating means of training both non-specialist health professionals and GPs to deliver CBT.

Adolescent↗
PubMed2003

[Analysis of additive and AE interaction effects of QTLs controlling plant height, heading date and panicle number in rice (Oryza sativa L.)].

Plant height (PH), heading date (HD) and productive panicle number (PN) are important agronomic trait in rice. Appropriate plant height, heading date and panicle number are prerequisites for the desired high and stable yield level in rice breeding programs. A recombinant inbred line (RIL) population consisting of 304 individuals was derived from a cross between indica varieties Zhong156 and Gumei2, from which a linkage map consisting of 168 RFLP, SSLP, RAPD and RGA markers that distribute on all the 12 rice chromosomes was constructed, and covers 1447.9 cM of the rice genome. The parents and 304 F9 lines were grown in the paddy field in China National Rice Research Institute (CNRRI), Hangzhou, China in 2001. The experiments were carried out in two seasons followed a randomized complete block design. QTLMapper 1.01 was applied to detect QTLs and QTL x environment (QE) interaction for HD (heading data), PH (plant height) and PN (panicle number), and conditional mapping for PH and PN was performed as well. A total of 15 QTLs with significant additive effects were detected, among which 4 QTLs had significant QE interaction. Ten QTLs with additive x additive epistatic effects for PH, HD and PN were detected, among which none showed significant epistatisis x environment interaction. These QTLs explained 12.12%, 1.38% and 5.00% of the total phenotypic variance for PH, HD and PN, respectively, and contributions were generally lower due to the strong epistatic effects. In conditional QTL analysis, the numbers of QTLs showing significant additive and epistatic effects were 7 and 6 for PH, and 3 and 3 for PN, respectively. Among the QTLs having significant additive effects for PH, qPH7-2 showed both additive effects and QE interaction, qPH7-1 and qPH10 showed QE interaction only, and the remaining 4 QTLs showed additive effects only. Each of the 3 QTLs having significant additive effects for PN did not display significant QE interaction. No epistatic QE interactions was detected. In addition, conditional QTL analysis indicated that the expression of QTLs for PH and PN may vary depending on the QTLs for HD.

Breeding↗
PubMedDate not supplied

Stability of drug additives to peritoneal dialysate.

OBJECTIVE: The primary literature was reviewed to determine the stability of drug additives in peritoneal dialysis solutions. DATA SOURCES: A MEDLINE search and retrieval, covering the period 1981 to 1994, was undertaken to identify relevant original literature. Additional references were identified from citations within the original literature. Non-English literature was excluded unless an English abstract was provided. STUDY SELECTION: Forty-nine studies were identified. Of these, 24 were directly related to drug stability, 13 were related to the clinical use of the drug additives but included no stability data, and 12 examined other, nonstability aspects of in vitro activity of antibiotics, additives, or drug adsorption in peritoneal dialysis bags and tubing. DATA EXTRACTION: Data included concentrations of drug additives and dialysate solutions, duration and temperatures of storage conditions, types of assay, and whether they were stability-indicating. RESULTS: Stability was defined as the duration of time that the drug concentration remained at 90% or more of the original concentration. Stability was examined under a large variety of conditions. Thirty-one drugs were identified from 20 manuscripts as single-drug additives. Most beta-lactams were stable for 1-2 weeks in a refrigerator and for several days at room temperature. Aminoglycosides were stable for 1-2 days at room temperature. Glycopeptides were stable for several weeks refrigerated or at room temperature. Prolonged storage at room temperature resulted in instability of cefotaxime, ceftazidime, ceftriaxone, and miconazole. Eleven drugs were identified from seven manuscripts as drug combination studies and showed similar stability as single agents. Dialysate concentration appeared to have minimal effect on stability. CONCLUSIONS: Drug additives in peritoneal dialysate, singly or combined, should be avoided unless data are available to support their stability. Additives should be made as close as possible to the time of the exchange. Alternatively, additives should be stored refrigerated, then warmed prior to use. The practice of preparing numerous bags at one time should be avoided. Finally, stability data do not indicate sterile integrity of the dialysate.

Adsorption↗
PubMed2004

Assessment of the influence of energy under-reporting on intake estimates of four food additives.

Under-reporting has been identified as an important source of uncertainty in food chemical exposure assessments. The objective of the present study was to assess the influence of under-reporting on food additive intake estimates. Dietary survey data were derived from the North-South Ireland Food Consumption Survey (2001). Data from the Republic of Ireland (n = 958) were used. Energy under-reporters were identified using a ratio of energy intakes to estimated basal metabolic rate. First, food categories (n = 26) included in an assessment of exposure of four food additives were created and patterns of food intakes (i.e. likelihood of consumption, frequency of consumption and reported portion size) between acceptable and under-reporters compared. Second, for each food additive, deterministic intake estimates for the total sample (i.e. acceptable and under-reporters), under-reporters and acceptable reporters were calculated and compared. Differential reporting of the majority of food categories between acceptable and under-reporters was recorded. Under-reporters were less likely to record the consumption of a given food and more likely to under-report the frequency of consumption and portion size compared with acceptable reporters. Food additive intake estimates amongst acceptable reporters were higher than corresponding intake estimates amongst the total sample of reporters and amongst under-reporters. With the exception of one food additive (erythrosine), ratios of upper percentile additive intakes amongst acceptable reporters to corresponding intake estimates amongst the total sample of reporters did not exceed 1.06 when results were expressed as total population or consumer-only intakes. Findings illustrated that energy under-reporting does not materially influence estimates of food additive exposure based on the four food additives studied. However, a number of situations were identified where the under-reporting might exert a more significant impact on resulting exposure estimates.

Bixaceae↗
PubMed1987

Oral challenge with food additives.

A randomized, placebo-controlled oral challenge with food additives (preservatives and food colorings) was carried out in 101 patients with eczema of undetermined origin who suspected that the intake of certain foods aggravated their dermatitis. 37 reacted to 1 or more of the food additives but not to a placebo, while 16 reacted to the placebo, or both the placebo and food additives. 48 had no reactions. The difference between the number of reactions to the food additives and the number of reactions to the placebo was not statistically significant. The reactions could be reproduced in only 1/3 of those challenged twice. It was not possible to correlate the reactions to food additives to reactivity to specific foodstuffs containing the same additives. If intolerance to food additives is suspected, an elimination diet seems warranted, regardless of whether the patient reacts to oral challenge with food additives.

Administration, Oral↗
PubMed1988

[Effect of the incorporation of additives on the aging of corn starch gels and "arepas"].

This research was carried out to investigate the effect of the incorporation of various additives on the ageing of corn starch and arepas. Starches were extracted from the endosperm of degerminated corn by a wet milling process, and its retrogradation, with or without the incorporation of additives was evaluated using the Brabender amilograph and by measuring the viscosity changes of the starch gels through time, using a Brookfield viscometer model RVT. The most effective additives in retarding the rate of ageing of starch gels, were used in the arepas. Likewise, trained panelists were utilized to find the levels of the additives incorporated in the arepas, by running taste threshold tests for each one of the additives. Textural changes of the arepas--maintained at two different storage temperatures, 9 degrees and 23 degrees C--were evaluated using an Instron texturometer. Preliminary tests with the corn starch allowed to choose the following additives: distilled monoglicerides, guar gum and hydrogenated vegetable oil. The effect of 15 different combinations of these additives on the texture of arepas was then studied, and findings revealed that only three of them were able to totally revert the retrogradation process, and maintain the hardness and elasticity within the expected range of a fresh-made arepa, when this is reheated until reaching a maximum temperature of 49 degrees C. A 66% of the hardening of the arepas prepared without additives can be reverted with the reheating process, but only if the product has not suffered dehydration. When stored for 24 hours at room temperature, unpacked arepas have a surface moisture loss of 47%, and even if reheated, hardening becomes irreversible in 84.6% of them.

Food Additives↗
PubMed2006

Addition of drug/s to a chemotherapy regimen for metastatic breast cancer.

BACKGROUND: The addition of a chemotherapy drug or drugs to an established regimen is one method used to increase the dose and intensity of treatment for metastatic breast cancer. OBJECTIVES: To identify and review the randomised trial evidence in the first line management of women with metastatic breast cancer that evaluates the addition of one or more chemotherapy drugs to an established regimen. SEARCH STRATEGY: We searched the specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group on 3rd August 2004 (updated search on 2nd August 2005) using the codes for "advanced breast cancer" and "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library. SELECTION CRITERIA: Randomised trials that evaluated a first line regimen of at least two chemotherapy drugs, and compared it to that same regimen plus the addition of one or more chemotherapy drugs in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: We collected data from published trials and assessed studies for eligibility and quality. Two reviewers extracted data independently. We derived hazard ratios (HR) from time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. We analysed response rates as dichotomous variables and extracted toxicity data where available. MAIN RESULTS: We identified 17 trials reporting on 22 treatment comparisons (2674 patients randomised). Fifteen trials (20 treatment comparisons) reported results for tumour response and 11 trials (14 treatment comparisons) published time-to-event data for overall survival. There were 1532 deaths in 2116 women randomised to trials of the addition of a drug to the regimen and control (the regimen alone). There was no detectable difference in overall survival between these patients, with an overall HR of 0.96 (95% CI 0.87 to 1.07, P = 0.47) and no statistically significant heterogeneity. We found no difference in time to progression between these regimens, with an overall HR of 0.93 (95% CI 0.81 to 1.07, P = 0.31) and no statistically significant heterogeneity. Addition of a drug to the regimen was favourably associated with overall tumour response rates (OR 1.21, 95% CI 1.01 to 1.44, P = 0.04) although we observed statistically significant heterogeneity for this outcome across the trials. Where measured, acute toxicities such as alopecia, nausea and vomiting and leukopenia were more common with the addition of a drug. AUTHORS' CONCLUSIONS: The addition of one or more drugs to the regimen shows a statistically significant advantage for tumour response in women with metastatic breast cancer but the results suggest no difference in survival time or time to progression. The positive effect on tumour response observed with addition of a drug to the regimen was also associated with increased toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Rate and mechanism of the oxidative addition of phenyl iodide to Pd0 ligated by triphenylarsine: evidence for the formation of a T-shaped complex.

The oxidative addition of phenyl iodide to the palladium(o) generated from [Pd0(dba)2] and n equivalents of AsPh3 (the most efficient catalytic precursor in Stille reactions) proceeds from [(solv)Pd0(AsPh3)2] (solv= solvent). However, the latter is present only in trace concentrations because it is involved in an equilibrium with the major, but nonreactive, complex [Pd0(dba)(AsPh3)2]. As regards the phosphine ligands, dba has a decelerating effect on the rate of the oxidative addition by decreasing the concentration of the reactive species. Relative to PPh3, the effect of AsPh3 is to increase the rate of the oxidative addition of PhI by a factor ten in DMF and seven in THF, independent of the value of n, provided that n > or = 2. In contrast to PPh3, the addition of more than two equivalents of AsPh3 to [Pd0(dba)2] (dba= trans,trans-dibenzylideneacetone) does not affect the kinetics of the oxidative addition because of the very endergonic displacement of dba from [Pd0(dba)(AsPh3)2] to form [Pd0(AsPh3)3]. The complex trans-[PhPdI(AsPh3)2], formed in the oxidative addition, is involved in a slow equilibrium with the T-shaped complex [PhPdI(AsPh3)] after appreciable decomplexation of one AsPh3. Under catalytic conditions, that is, in the presence of a nucleophile, such as CH2=CH-SnBu3 which is able to coordinate to [Pd0(AsPh3)2], a new Pd0 complex is formed: [Pd0(eta2-CH2=CHSnBu3)(AsPh3)2]; however, this complex does not react with PhI. Consequently, CH2=CH-SnBu3 slows down the oxidative addition by decreasing the concentration of the reactive species [(solv)Pd0(AsPh3)2]. This demonstrates that a nucleophile may be not only involved in the transmetallation step, but may also interfere in the kinetics of the oxidative addition step by decreasing the concentration of reactive Pd0.

Journal Article↗
PubMed2003

Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes.

Representative diastereomeric, erythritol and threitol polyhydroxylated pyrrolidine imine scaffolds have been rapidly elaborated to diversely functionalized aza-sugars through highly diastereoselective organometallic (RM) additions (R=Me, Et, allyl, hexenyl, Ph, Bn, pMeO-Bn). The yields for these additions have all been substantially enhanced from previously optimised levels (<58 %) for normal additions using a reverse addition procedure (e.g. R=Ph; 44 % normal mode --> 78 % reverse mode). The high diastereoselectivities (>98 % de for all except R=Me) are consistent with additions that are controlled by the configuration of the C-2 centre adjacent to the azomethine imine carbon and the conformation of the pyrrolidine imine. The high potential of this method was demonstrated by concise syntheses of 1-epi- and 2-epi-desacetylanisomycins. In addition, the late stage addition of hydrophobic substituents, which this imine addition methodology allows, enabled the preparation of novel aza-sugars with enhanced inhibitory potential. This was highlighted by the screening of a representative selection of these "hydrophobically-modified" aza-sugars against a diverse panel of 12 non-mammalian and human carbohydrate-processing enzymes. This identified a novel nanomolar alpha-galactosidase inhibitor (IC(50)=250 nM) and a novel highly selective glucosylceramide synthase inhibitor (IC(50)=52 microM, no alpha-glucosidase inhibition at 1 mM). Furthermore, analysis of the structure-activity relationships of racemic series of inhibitors allowed some validation of Fleet's mirror-image enzyme active site postulate.

Journal Article↗
PubMed2005

Chemo- and periselectivity in the addition of [OsO2(CH2)2] to ethylene: a theoretical study.

Quantum chemical calculations by using density functional theory at the B3LYP level have been carried out to elucidate the reaction course for the addition of ethylene to [OsO2(CH2)2] (1). The calculations predict that the kinetically most favorable reaction proceeds with an activation barrier of 8.1 kcal mol(-1) via [3+2] addition across the O=Os=CH2 moiety. This reaction is -42.4 kcal mol(-1) exothermic. Alternatively, the [3+2] addition to the H2C=Os=CH2 fragment of 1 leads to the most stable addition product 4 (-72.7 kcal mol(-1)), yet this process has a higher activation barrier (13.0 kcal mol(-1)). The [3+2] addition to the O=Os=O fragment yielding 2 is kinetically (27.5 kcal mol(-1)) and thermodynamically (-7.0 kcal mol(-1)) the least favorable [3+2] reaction. The formal [2+2] addition to the Os=O and Os=CH2 double bonds proceeds by initial rearrangement of 1 to the metallaoxirane 1 a. The rearrangement 1-->1 a and the following [2+2] additions have significantly higher activation barriers (>30 kcal mol(-1)) than the [3+2] reactions. Another isomer of 1 is the dioxoosmacyclopropane 1 b, which is 56.2 kcal mol(-1) lower in energy than 1. The activation barrier for the 1-->1 b isomerization is 15.7 kcal mol(-1). The calculations predict that there are no energetically favorable addition reactions of ethylene with 1 b. The isomeric form 1 c containing a peroxo group is too high in energy to be relevant for the reaction course. The accuracy of the B3LYP results is corroborated by high level post-HF CCSD(T) calculations for a subset of species.

Journal Article↗
PubMed1993

Attachment and proliferation of bovine aortic endothelial cells onto additive modified poly(ether urethane ureas).

To better understand endothelial cell interactions with poly(ether urethane urea) (PEUU) materials, and to assess bovine aortic endothelial cell attachment, films were incubated for 24 h with BAEC in media containing 5% fetal bovine serum. Other films were allowed to incubate for 4 more days in media containing 5% fetal bovine serum without cells to assess BAEC proliferation. The assay was performed on PEUU films modified with acrylate and methacrylate polymer and copolymer additives that spanned a wide range on the hydrophobicity/hydrophilicity scale. Tissue culture polystyrene (TCPS) was used as a control. The assay showed that PEUU films loaded with Methacrol 2138F [copoly(diisopropylaminoethyl methacrylate [DI-PAM]/decyl methacrylate [DM]) (3/1)] or with its hydrophilic component, DIPAM, in homopolymer form (i.e., h-DIPAM), significantly enhanced BAEC attachment (approximately 80% of TCPS values) and proliferation (approximately 80%) when compared to unloaded PEUU films (attachment 73%; proliferation, 47%) or to PEUU films loaded with the more hydrophobic acrylate or methacrylate polymer additives (attachment, 32-69%; proliferation, 18-57%). The assay also showed that PEUU films coated with homopoly(diisopropylaminoethyl acrylate) (h-DIPAA) significantly enhanced BAEC attachment and proliferation when compared to PEUU films coated with h-decyl acrylate (h-DA); films coated with the copolymer of these two acrylates (i.e., co-[DIPAA/DA] [3/1]) showed intermediate behavior. To explain the enhancement of BAEC interaction with films loaded with Methacrol 2138F or h-DIPAM, when compared to unmodified PEUU films or to PEUU films loaded with more hydrophobic acrylate and methacrylate polymer additives, it was assumed that the additives near the surface region of the solvent swollen PEUU matrix may have migrated to, or near to, the PEUU-air interface during film formation, creating an additive enriched PEUU surface region. It is suggested that, once at this surface region, dynamic reorientation in response to an aqueous medium ensured the additives were able significantly to influence protein adsorption, and concomitant endothelial cell behavior, but only if they interacted with aqueous media more favorably than the PEUU. The ability of Methacrol and h-DIPAM additives to enhance endothelial cell behavior is argued to be the result of increased hydrophilicity. This is the result of exposed, hydrogen-bonding DIPAM moieties and increased surface flexibility, which is itself due to the hydration of unhindered Methacrol chains, which may create an additive enriched PEUU-water interfacial zone.

Animals↗
PubMed1984

Effect of nitroglycerin-soluble additives on the stability of molded nitroglycerin tablets.

Nitroglycerin vapor pressures at 25 degrees C were determined for additive-nitroglycerin systems over the additive-nitroglycerin weight ratio range of 0.5 to 3.0 for 16 additives exhibiting solubility in nitroglycerin. The effects of the additives on nitroglycerin chemical stability at 25 degrees C and 50 degrees C were also studied. Tablet stability characteristics, i.e., content uniformity, open-dish stability, and chemical decomposition were evaluated for selected tablet formulations. Most additives lowered the vapor pressure of nitroglycerin sufficiently to stabilize content uniformity when used at additive-nitroglycerin weight ratios near 1. Higher additive levels are needed for significant potency stabilization in open-dish stability tests, but these levels normally decrease the chemical stability of nitroglycerin. However, stabilization of content uniformity, a twofold reduction of potency loss in an open-dish stability test, and chemical stability are possible with at least three of the additives studied.

Absorption↗
PubMed1980

Quantitative estimation of overadditive and underadditive drug effects by means of theoretical, additive dose-response curves.

A graphical method is described that permits simple and adequate quantitative and statistical evaluation of combinations of synergistically acting drugs. Thereby, the dose-response (DR) of a drug A can be determined in the presence as well as in the absence of a certain concentration of a drug B. The effects of A + B combined are expressed as combined (total) effects related to the control value before addition of B. The DR curve obtained in this manner is compared with a theoretical DR curve of additive synergism, which can be constructed simply. This procedure allows differentiation of overadditive or underadditive from additive interactions of A + B and the quantitation of nonadditive drug effects. DR curves of additive interaction coincide with the respective theoretical additive DR curve. Overadditive DR curves are characterized by a left shift from the theoretical additive DR curve that can be expressed by a dose factor. Increased maximum effects of A + B over A can be treated statistically (t-test). Underadditive DR curves show a shift to the right from the theoretical additive DR curve that can likewise be expressed by a dose factor. Decreased effects of A + B below the maximum of A can likewise be treated by t-test. The quantitative expression of overadditive drug interactions further allows differentiation between sequential and functional synergism, the DR curve of the latter can also be constructed simply. The application of this method to experiments with isolated coronary arteries had yielded examples of additive, overadditive, and underadditive drug interactions. The method appears to be a superior alternative to the isoboles method of Loewe and Muischnek (1926).

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