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Biomedical subjects

A Rubinstein

Publications and source records attributed to A Rubinstein.

At least 37 records · Page 2Linked to original sources
PubMed2000

Phosphated crosslinked guar for colon-specific drug delivery. I. Preparation and physicochemical characterization.

Guar gum (GG) was crosslinked with increasing amounts of trisodium trimetaphosophate (STMP) to reduce its swelling properties for use as a vehicle in oral delivery formulations, especially drug delivery systems aimed at localizing drugs in the distal portions of the small bowel. Swelling of GG in artificial gastrointestinal fluids was reduced from 100 to 120-fold (native GG) to 10-35-fold depending on the amount of crosslinker used, showing a bell-shape dependency. As a result of the crosslinking procedure GG lost its non-ionic nature and became negatively charged. This was demonstrated by methylene blue (MB) adsorption studies and swelling studies in sodium chloride solutions with increasing concentrations in which the hydrogels' network collapsed. The adsorption of MB was also used to characterize the degree of the GG crosslinking, from which the effective network density was calculated. In addition, effective network density was calculated from elasticity measurements. Both measurements showed that the crosslinking density (but not swelling) of the new products was linearly dependent on the amount of STMP used in the reaction.

Adsorption↗
PubMed2000

Phosphated crosslinked guar for colon-specific drug delivery. II. In vitro and in vivo evaluation in the rat.

Targeting of drugs to the colon, following oral administration, can be accomplished by the use of modified, biodegradable polysaccharides as vehicles. In a previous study, a crosslinked low swelling guar gum (GG) hydrogel was synthesized by reacting it with trisodium trimetaphosphate (STMP). In the present study the functioning of GG crosslinked products (GGP) as possible colon-specific drug carriers was analyzed by studying (a) the release kinetics of pre-loaded hydrocortisone from GGP hydrogels into buffer solutions with, or without GG degrading enzymes (alpha-galactosidase and beta-mannanase) and (b) direct measurements of the polymers' degradation in the cecum of conscious rats. The effect of GG diet on alpha-galactosidase and beta-mannanase activity in the cecum of the rat and GGP degradation was also measured. It was found that the product GGP-0.1 (loosely crosslinked with 0.1 equivalents of STMP) was able to prevent the release of 80% of its hydrocortisone load for at least 6 h in PBS, pH=6.4. When a mixture of alpha-galactosidase and beta-mannanase was added to the buffer solution, an enhanced hydrocortisone release was observed. In-vivo degradation studies in the rat cecum showed that despite the chemical modification of GG, it retained its enzyme-degrading properties in a crosslinker concentration-dependent manner. Eight days of GG diet prior to the study increased alpha-galactosidase activity in the cecum of the rat three-fold, compared to its activity without the diet. However, this increase in the enzyme activity was unable to improve the degradation of the different GGP products. The overall alpha-galactosidase activity in the rat cecum was found to be extracellular, while the activity of beta-mannanase was found to be bacterial cell-wall associated. It is concluded that because CG crosslinked with STMP can be biodegraded enzymatically and is able to retard the release of a low water-soluble drug, this polymer could potentially be used as a vehicle for colon-specific drug delivery.

Animals↗
PubMed2000

Relation between colonic inflammation severity and total low-molecular-weight antioxidant profiles in experimental colitis.

Tissue antioxidant status is altered as a response to oxidative stress. This oxidative stress, caused by reactive oxygen species, is associated with inflammatory bowel disease (IBD). Our aim was to examine the relationship between total tissue low-molecular-weight antioxidant (LMWA) profile and inflammation severity in dinitrobenzene sulfonic acid (DNBS) experimental colitis in the rat. Rats were treated with three doses of DNBS: 1, 10, and 20 mg. Inflammation severity was assessed by tissue colonic wet weight, macroscopic evaluation, and tissue myeloperoxidase (MPO) activity. The capacity of water-soluble LMWA was assessed by measuring the reducing power of the tissues with cyclic voltammetry (CV) and by measuring tissue levels of reduced glutathione. While typical markers of inflammation (MPO, macroscopic examination, and colonic wet weight) indicated DNBS dose dependency, such dependency could not be demonstrated for the tissue LMWA as measured by reduced glutathione levels and by the tissues' reducing power. Mild colonic inflammation (induced by ethanol or by 1 mg of DNBS) caused an increase in the overall capacity of water-soluble LMWA. However, severe inflammation (induced by 20 mg of DNBS) caused a reduction in the tissue LMWA capacity. An intermediate dose of DNBS (10 mg) caused moderate inflammation, but did not cause a significant change in the tissue LMWA compared with a saline control treatment. In conclusion, LMWA changed in a biphasic pattern reflective of the severity of mucosal colonic inflammation. It is suggested that: low dose of DNBS (1 mg) and topical alcohol (25% v/v) caused an adaptation effect to the mild oxidative stress associated with mild inflammation. This resulted in an increase in the LMWA. A higher dose of DNBS (20 mg) caused more severe inflammation with an overall reduction in LMWA. The increased efflux of reactive oxygen species, associated with severe inflammation, led to an overall consumption of the tissue LMWA, which masked the increase in LMWA caused by the mild oxidative stress.

Animals↗
PubMed2000

The effect of local attachment of cationized antioxidant enzymes on experimental colitis in the rat.

PURPOSE: To investigate the possibility of local treatment of colitis with the adhesive antioxidant enzymes catalase and superoxide dismutase (SOD). METHODS: The net electric charge of the enzymes' surfaces was modified from negative to positive, to cause their adherence to the colon epithelium. The effects of this local administration were assessed in inflamed rat colon. Inflammation severity (colitis) was assessed by measuring colonic tissue myeloperoxidase (MPO) activity, amounts of tumour necrosis factor alpha (TNFalpha) and concentrations of reduced glutathione (GSH). The measurements were carried out in two types of protocols: preventive (pre-colitis induction) and treatment (post-colitis induction). In addition, the efficacy of treatment with the cationized enzymes was compared to 5-aminosalicylic acid (5-ASA) and betamethasone with similar administration routes. RESULTS: The two cationized antioxidant enzymes were found to be efficient in both prevention and treatment of experimental colitis. The two cationized enzymes caused a significant reduction in MPO activity. A reduction in TNFalpha concentration was noted only after the treatment protocol. No correlation was found between inflammation severity and tissue levels of GSH. In most cases the cationized enzymes were more effective than 5-ASA and betamethasone. CONCLUSION: Cationized catalase and cationized SOD have the potential to be efficient therapeutic tools in the local treatment of colitis.

Animals↗
PubMed2000

Synchronized release of sulpiride and sodium decanoate from HPMC matrices: a rational approach to enhance sulpiride absorption in the rat intestine.

PURPOSE: (a) To improve the absorption of sulpiride (SP) through the intestinal wall by incorporating it together with sodium decanoate (SD) into erodible matrices, designed to synchronize the release of SP and SD over different periods of time; (b) to test, in vivo the hypothesis that this simultaneous release increases SP absorption from the intestinal lumen. METHODS: Matrix tablets, possessing different erosion rates, were prepared by changing the ratios between SD and hydroxypropyl methylcellulose (HPMC). The amounts of HPMC varied from 2.5% to 17% w/w. Double layer tablets, containing similar amounts of SP, SD, and HPMC were used as nonsynchronous controls. The erosion kinetics of the tablets was assessed gravimetrically in vitro in USP basket dissolution apparatus and in vivo in the intestine of the anesthetized rat after intra-intestinal administration. SP absorption was studied after intra-intestinal administration of the different kinds of tablets to anesthetized rats, by monitoring SP blood levels. SP and SD levels in the withdrawn samples from the dissolution systems and blood were analyzed by HPLC. RESULTS: The controlled erosion of the tablets resulted in equal release rates of SP and SD during the initial linear phase of the process. This synchronized release lasted over different time periods depending on the relative amount of HPMC in the formulations (from 1 hour to 4 hours for 2.5 and 17 % w/w of HPMC, respectively). The synchronous matrices increased SP bioavailability after intra-intestinal administration. The increase varied from 1.4 to 2.3-fold for the slow and the fast release formulations, respectively (compared with the nonsynchronous, SD containing control formulations), indicating the ability to control both erosion rate and length of intestinal segment in which absorption is taking place. CONCLUSIONS: SP bioavailability after intestinal administration can be improved only if SP is released together with SD along the entire intestinal route. This can be accomplished by the design of synchronous matrices capable of concomitant release of SP and SD despite the differences in their water solubility. The ability to manipulate and control the duration of the synchronous phase of the matrices makes it possible for SP to be absorbed at different parts of the intestine.

Animals↗
PubMed2000

Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety.

OBJECTIVE: To determine the efficacy and safety of a statin-fibrate combination in diabetes patients. DESIGN.: An open 21-month trial in which each patient first received the single drug for 6 months and then a combination of the two for 1 year. SETTING: Three lipid clinics in university-based tertiary care hospitals. PATIENTS: One hundred and forty-eight patients with type 2 (non-insulin-dependent, NIDDM) diabetes mellitus under stable control for 3 months by means of diet and oral hypoglycaemic medication. INTERVENTION: Patients from one clinic (n = 48) received bezafibrate slow release (400 mg day-1), and patients from the other two clinics (n = 100) received simvastatin 20 mg day-1. Six months later, all patients were switched to a daily combination of 400 mg bezafibrate slow release and 20 mg simvastatin for 1 year. RESULTS: The combination of statin and fibrate led to a 23% reduction in total cholesterol, 42% reduction in triglycerides, 29% reduction in LDL-c, 25% increase in HDL-c, 10% decrease in fibrinogen and 19% reduction of Lp(a) levels, and a decrease in the cholesterol/HDL-c ratio (from 8.9 to 5.4) in all 148 patients. Cardiovascular (CV) event rate was significantly reduced from 9.5% during the first 6 months of the study to less than 2% during the last year of the study (whilst on combination Rx). Side-effects with all treatments included only two patients who developed myopathy when on the combined regimen and one on the single statin regimen. However, plasma creatinine phosphokinase (CPK) levels doubled (but remained within the normal range) in most of the patients on combination therapy, compared with only a mild increase in patients receiving a single medication. CONCLUSIONS: The statin and fibrate combination was found to be more efficacious than a single medication for treatment of diabetic dyslipidaemia, as evidenced by improvement in the lipoprotein profile, reductions in Lp(a), fibrinogen and CV event rate, and almost no clinically significant side-effects.

Aged↗
PubMed2000

Anticipatory strategy training: implications for the postlingually hearing-impaired adult.

The present study was designed to determine if speech recognition performance will improve after subjects prepare for an unfamiliar communication situation as opposed to a familiar one. Forty-five normal-hearing subjects were divided into three groups: one trained using a well-known fairytale, one trained using an obscure fable, and one without training. Post-training, all groups performed similarly when tested on the familiar tale. When test material involved the unfamiliar fable, only the group trained on that material obtained significantly better scores than the other groups. Results support teaching clients that increasing their knowledge of upcoming unfamiliar events can improve subsequent speech recognition.

Adult↗
PubMed2000

Drug targeting by surface cationization.

Cationization of drug products and carriers involves a direct modification or attachment of conveying or accompanying components, either of which cause a charge modification. Cationization of macromolecules such as proteins and nucleotides and particulate drug carriers generally enhances their cellular uptake by endocytosis. The most common use of cationization today is in gene delivery. This is undertaken by either employing cationic polymers or entraping nucleotides in cationic carriers such as cationic liposomes. Cationized delivery systems are also used to overcome biological barriers and are suggested for drug targeting, in a nonspecific manner, to a variety of body organs, including brain, eyes, nose, and inflamed intestinal epithelium. Protein cationization is also suggested both for tumor immunotherapy and as a diagnostic tool in cancer therapy. Cationization has proven itself to be a straightforward tool for targeting to cells, tissues, and selected organs. This article reviews the extensive range of applications of cationization for improving drug and gene delivery and summarizes major technologies employed for that purpose.

Animals↗
PubMed1999

Immunologic responses of HIV-1-infected study subjects to immunization with a mixture of peptide protein derivative-V3 loop peptide conjugates.

V3 loop peptide sequences from several HIV-1 strains were covalently linked to purified protein derivative (PPD) of Mycobacterium tuberculosis. A mixture of PPD conjugates of V3 loop peptides from six different strains of HIV-1 induced a stronger antibody response than a single V3 peptide-conjugate administered to guinea pigs and humans. Sera from animals immunized with a PPD-six peptide-PPD conjugate neutralized multiple primary-isolate strains of HIV-1. Potent immune responses were noted only when animals were primed with bacillus Calmette-Guerin (BCG), PPD was covalently bound to the peptides, and PPD was used as the carrier protein. Based on these animal studies, an immunogen consisting of PPD-conjugated V3 loop peptides from five HIV-1 strains was tested in 7 HIV-1 seropositive PPD skin test positive study subjects. Vaccinees exhibited over time a uniform increase in neutralizing antibodies for both laboratory adapted and primary isolates of HIV-1, including strains from multiple clades. In 3 patients with baseline viral loads between 8000 and 12,000 RNA copies/ml, the viral load declined in 2 patients to <400 copies/ml and in 1 patient to 1200 copies/ml without concurrent administration of highly active antiretroviral therapy (HAART).

AIDS Vaccines↗
PubMed1999

Hormone replacement therapy enhances postprandial lipid metabolism in postmenopausal women.

Postmenopausal estrogen therapy reduces cardiovascular morbidity and mortality, except in women with advanced coronary disease. This beneficial effect is partly attributed to a reduction of fasting plasma total and low-density lipoprotein cholesterol (LDL-C) and an elevation of plasma high-density lipoprotein cholesterol (HDL-C) concentrations. Since postprandial lipemia seems to play a role in the pathogenesis of coronary artery disease, we evaluated the effect of hormone replacement therapy (HRT) on postprandial lipoprotein metabolism in 14 normolipemic postmenopausal women. A vitamin A fat-loading test before and after three cycles of treatment with a sequential combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) was used to label chylomicrons and chylomicron remnants with retinyl palmitate (RP), and RP clearance was assessed over an 8-hour period postprandially. Following 3 months of HRT, fasting total cholesterol and LDL-C levels were reduced 9.8% (P = .049) and 16.5% (P = .023), respectively. Fasting HDL-C levels increased 18.9% (P = .001). Fasting triglycerides (TGs) increased, but not significantly. Postprandial integrated plasma TGs did not change significantly. The integrated RP levels in whole plasma and chylomicron (Svedberg flotation units [Sf] > 1,000) and nonchylomicron (Sf < 1,000) fractions were reduced 58% (P = .043), 78% (P = .041), and 75% (P = .001), respectively, after hormonal treatment. Enhanced clearance of chylomicrons and chylomicron remnants by HRT may contribute to the protective effect of estrogens against cardiovascular disease in normolipemic postmenopausal women.

Chylomicrons↗
PubMed1999

Changes in immune activation markers during pregnancy and postpartum.

Changes in CD4 + cell levels and other immune parameters have been reported to occur during pregnancy but the timing of these alterations and their relationship to changes in immune function have not been well characterized. In addition, the influence of sociodemographic, obstetric, and other covariates on these relationships is largely unknown. We measured three immune activation markers, soluble interleukin-2 receptor (sIL-2Ralpha), soluble CD8 antigen (sCD8), and neopterin during pregnancy and postpartum in 170 HIV-1-seronegative women enrolled in the Mothers and Infants Cohort Study. Ante-partum and postpartum changes in these markers were examined using multivariable longitudinal random effects models. Neopterin levels began to rise well before delivery and were in decline by 2 months postpartum. sIL-2Ralpha and sCD8 levels increased at or near delivery and peaked by 2 months postpartum. After adjustment for other variables, the peak in sIL-2Ralpha was greater among women with pre-term than full-term deliveries (P = 0.05). All three markers were higher in whites than non-whites and in 'hard' drug users than non-users (P < or = 0.001 for each). After adjustment for these and other variables, hepatitis C virus (HCV) seropositivity was associated with higher levels of sCD8 and neopterin (P < or = 0.001 for each) but not sIL-2Ralpha (P = 0.27). These longitudinal data indicate that a state of broad immune activation develops at or near delivery. A number of maternal variables appear to influence the magnitude of these changes.

Adult↗
PubMed1999

Differences in the reducing power along the rat GI tract: lower antioxidant capacity of the colon.

The ability of the gastrointestinal (GI) tract, as well as other tissues, to cope with reactive oxygen species (ROS) efflux in pathological events is determined partly by epithelial antioxidant levels. These levels are comprised of tissue antioxidant enzymes and low molecular weight antioxidants (LMWA). While glutathione levels and the activity of enzymatic antioxidants along the GI tract have been studied, the contribution of the overall LMWA to the total antioxidant capacity has not yet been determined. In this study the overall antioxidant activity in the mucosa/submucosa and muscularis/serosa of various sections along the small intestine and colon of the rat was evaluated by determining the reducing power, which reflects the total antioxidant activity derived from LMWA, using cyclic voltammetry. The activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase was also measured. The reducing power (total antioxidant activity) was higher in the mucosa/submucosa of the small intestine as compared to the mucosa/submucosa of the colon. Similarly, catalase and SOD activity in the mucosa/submucosa of the small intestine was significantly higher than in the mucosa/submucosa of the colon. Differences were also observed in the reducing power and SOD activity in the muscularis/serosa of the rat small intestine as compared to the colon. The low antioxidant capacity in the colon may facilitate reactive oxygen species (ROS)-mediated injury and lead to inflammatory diseases such as ulcerative colitis, specifically in the colon.

Animals↗
PubMed1999

Development and psychometric testing of a quality of recovery score after general anesthesia and surgery in adults.

UNLABELLED: A variety of methods have been used to quantify aspects of recovery after anesthesia. Most are narrowly focused, are not patient-rated, and have not been validated. We therefore set out to develop a patient-rated quality of recovery score. We constructed a 61-item questionnaire that asked individuals (patients and relatives, medical and nursing staff; total n = 136) to rate various postoperative items describing features a patient may experience postoperatively. The most highly ranked items were included in a final nine-point index score, which we called the "QoR Score." We then studied two cohorts of surgical patients (n = 449). There was good convergent validity between the QoR Score and the visual analog scale score (rho = 0.55, P < 0.0001). Discriminant construct validity was supported by comparing resultant QoR Scores in patients undergoing day-stay, minor, and major surgery (P = 0.008), as well as a negative correlation with duration of hospital stay (rho = -0.20, P < 0.0001), and, using multivariate regression, demonstrating a significant negative relationship between QoR Score and female gender (P = 0.048) and older age (P = 0.041). There was also good interrater agreement (rho = 0.55, P < 0.0001), test-retest reliability (median rho = 0.61, P < 0.0001), and internal consistency (alpha = 0.57 and 0.90, P < 0.0001). There was a significant difference between the groups of patients recovering from major and minor surgery (P < 0.001). This study demonstrates that the QoR Score has good validity, reliability, and clinical acceptability in patients undergoing many types of surgery. IMPLICATIONS: We set out to develop a patient-rated quality of recovery score (QoR) that could be used both as a measure of outcome in perioperative trials and for clinical audit. We first surveyed patients and staff to identify important aspects of recovery, then developed a nine-point QoR Score. This was then compared with other measures of postoperative outcome. We found that the QoR Score is a useful measure of recovery after anesthesia and surgery.

Adolescent↗
PubMed1999

Efficacy and safety of cerivastatin for type 2 diabetes and hypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators.

BACKGROUND: The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia. METHODS: This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks. RESULTS: Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period. CONCLUSIONS: Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials.

Adult↗
PubMed1999

Thyroxine replacement therapy enhances clearance of chylomicron remnants in patients with hypothyroidism.

To further confirm the benefit of replacement therapy in terms of risk for coronary artery disease, we evaluated the effect of T4 on postprandial lipoproteins in patients with hypothyroidism. Nine normolipidemic patients (aged 62.75+/-7.6 yr) with TSH of 32.2+/-13.2 mU/L and free T4 of 0.66+/-0.17 ng/mL were treated with T4 (50-100 microg/day) for at least 4 months. The behavior of postprandial lipoproteins was assessed before and during treatment by determining retinyl palmitate levels in the total plasma, chylomicrons (Sf >1000) and chylomicron remnants (Sf <1000) fractions for 8 h after a mixed meal plus vitamin A. During T4 treatment, serum levels of TSH and FT4 were 4.4+/-4.9 mU/L and 1.2+/-0.34 ng/mL (P = 0.001 and P = 0.002), respectively. Fasting low density lipoprotein cholesterol decreased from 166+/-35 to 135+/-23 mg/dL (P = 0.035). Retinyl palmitate (RP) levels in the chylomicron remnant fraction was reduced significantly during therapy from 6948+/-2790 to 5174+/-2401 microg/L x h (area under the curve +/-SD; P = 0.014). Total plasma RP and chylomicron RP remained unchanged. We conclude that T4 enhances the clearance of chylomicron remnants in normolipidemic patients with hypothyroidism.

Cholesterol, HDL↗