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Biomedical subjects

S Donoghue

Publications and source records attributed to S Donoghue.

At least 19 recordsLinked to original sources
PubMed2005

Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD.

BACKGROUND: Abeta42-immunization reduces plaque burden and improves cognition in transgenic mouse models of Alzheimer disease (AD). This phase 1 study evaluated the safety, tolerability, and immunogenicity of AN1792 (human aggregated Abeta42) in patients with mild to moderate AD. METHODS: Twenty patients were enrolled into each of four dose groups and randomly assigned to receive IM AN1792 (50 or 225 microg) with QS-21 adjuvant (50 or 100 microg) or QS-21 only (control) in a 4:1 active:control ratio on day 0 and at weeks 4, 12, and 24. Patients could receive up to four additional injections of a polysorbate 80 modified formulation at weeks 36, 48, 60, and 72. Safety, tolerability, immunogenicity, and exploratory evidence of efficacy were evaluated. RESULTS: Treatment-related adverse events were reported in 19 (23.8%) patients, but no relationship was observed between AN1792 dose and incidence. One patient developed meningoencephalitis that was diagnosed after death (not directly related to study treatment) and 219 days after discontinuing from the study. Five deaths occurred during the study follow-up, but none was considered to be directly related to study treatment. During the period of the first four injections, 23.4% of AN1792-treated patients had a positive anti-AN1792 antibody titer (an anti-AN1792 antibody titer of > or =1:1,000). This increased to 58.8% after additional injections with the modified formulation. Disability Assessment for Dementia scores showed less decline among active compared with control patients at week 84 (p = 0.002). No treatment differences were observed in three other efficacy measures. CONCLUSIONS: AN1792 + QS-21 elicited a positive antibody response to Abeta42 in more than half of this elderly study population.

Adjuvants, Immunologic↗
PubMed2002

A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin.

BACKGROUND: Alpha-4 integrins facilitate leucocyte migration across vascular endothelium. AIM: To assess the safety and efficacy of natalizumab (Antegren), a humanized antibody to alpha-4 integrin, in patients with active ulcerative colitis. METHODS: Ten patients with active ulcerative colitis, defined by a Powell-Tuck activity score > 4, received a single 3 mg/kg natalizumab infusion. The primary end-point was the change in Powell-Tuck score at 2 weeks post-infusion. RESULTS: Significant decreases in the median Powell-Tuck score were observed at 2 and 4 weeks post-infusion (7.5 and 6, respectively) compared to the median baseline score (10). Five of 10 patients achieved a good clinical response at 2 weeks and one more patient by 4 weeks, defined by a Powell-Tuck score of < or = 5. Significant improvements in quality of life scores were found at week 4. Rescue medication was required by two (20%), three (30%) and eight (80%) patients by weeks 2, 4 and 8, respectively (median, 34 days; range, 8-43 days). One patient remained in remission at 12 weeks. The median C-reactive protein at 2 weeks (6 mg/L) was lower than that pre-treatment (16 mg/L). CONCLUSIONS: A single 3 mg/kg infusion of natalizumab was well tolerated by ulcerative colitis patients. The positive efficacy demonstrated in this study merits further investigation by randomized, placebo-controlled trials.

Antibodies, Monoclonal↗
PubMed2001

A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease.

BACKGROUND & AIMS: alpha4 integrins are important mediators of leukocyte migration across vascular endothelium. This pilot placebo-controlled study aimed to assess the safety and efficacy of natalizumab, a recombinant humanized monoclonal antibody to alpha4 integrin, in patients with mild to moderately active Crohn's disease. METHODS: Thirty patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =151 and < or =450) received a 3-mg/kg infusion of natalizumab (n = 18) or placebo (n = 12) by double-blind randomization. The study's primary endpoint was change in CDAI at week 2. RESULTS: At week 2, the CDAI decreased significantly from baseline after infusion of natalizumab (mean 45 points) but not placebo (mean 11 points). Seven (39%) natalizumab-treated patients achieved remission at week 2, compared with 1 (8%) treated with placebo. In contrast, 4 (33%) of the placebo-treated patients required rescue medication by week 2, compared with 2 (11%) natalizumab-treated patients. Significant increases in circulating B and T lymphocytes were detected only after natalizumab administration. The frequency of commonly reported adverse events did not differ significantly between groups. CONCLUSIONS: A single 3-mg/kg natalizumab infusion was well tolerated by Crohn's disease patients, although the dose used may have been suboptimal. Elevated circulating lymphocyte levels after natalizumab suggest interrupted lymphocyte trafficking. Natalizumab therapy in active Crohn's disease merits further investigation.

Adult↗
PubMed2001

Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities?

OBJECTIVES: To assess use of antiretroviral therapy (ART) by HIV positive pregnant women in London since 1994 and the risk of congenital abnormalities associated with multidrug exposure during the first trimester of pregnancy. METHODS: Retrospective multicentre study of medical, obstetric, and paediatric notes of all mother-infant pairs, where the mother was known to be HIV infected before delivery, using a standardised proforma. RESULTS: In this study of 195 mother-infant pairs, use of ART during any stage of pregnancy increased from 33.3% in 1994 to 92.5% in 1999 (p=0.01, trend). First trimester exposure increased from 0% in 1994 to 27.5% in 1999 (p=0.00045, trend). Congenital malformations were observed in nine infants (4.6%). Compared with infants not exposed to ART or folate antagonists during the first trimester (n=148), exposure to both ART and folate antagonists during the first trimester (n=13) was associated with an increased risk of congenital abnormalities (4% v 23.1%; OR 7.10, 95% CI 1.5, 34.2). No malformations were observed in the 34 children exposed to either ART or folate antagonists alone during the first trimester. CONCLUSION: An increasing number of HIV infected women conceived while on ART. Although there is no evidence of teratogenicity caused by ART if given alone during the first trimester, exposure to the combination of ART and folate antagonists was associated with a significantly higher risk of congenital abnormalities in this cohort.

Abnormalities, Drug-Induced↗
PubMed2000

Drugs in development for the treatment of multiple sclerosis: antigen non-specific therapies--an update.

In the past few years there has been significant progress in the development of therapy for the treatment of relapsing remitting and secondary progressive multiple sclerosis. Research interest in multiple sclerosis (MS) therapeutics has remained high and clinical investigation into potential new therapies continues. This review summarises the advances with currently available therapies and briefly outlines the results from studies with other drugs being developed for the treatment of multiple sclerosis.

Adjuvants, Immunologic↗
PubMed1999

Immunohistochemical localization of caspase-3 correlates with clinical outcome in B-cell diffuse large-cell lymphoma.

Although B-cell diffuse large-cell lymphoma (DLCL) can respond to chemotherapy and radiotherapy, a large number of patients are still resistant to treatment. Caspase-3 is an enzyme crucial to the apoptotic process and may be important in the clinical outcome of these patients. The pattern of caspase-3 expression was studied in 54 cases of DLCL using immunohistochemistry and quantitative reverse-transcription PCR. Tumor cells displayed both a diffuse cytosolic and a punctate cytosolic staining for caspase-3. Kaplan-Meier survival curves indicated that tumor cells with a diffuse cytosolic expression of caspase-3 correlated with a poor prognosis (P > 0.0004). In addition, a punctate cellular localization was associated with complete response to treatment (P = 0.011). Cases with a small percentage of lymphoma cells expressing caspase-3 also tended to show poor survival (P > 0.09). Levels of caspase-3 mRNA were not significant (P > 0.17), although a weak trend was observed similar to the immunohistochemical analysis. The pattern of expression of caspase-3 was also assessed with respect to terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) positivity in both reactive lymph nodes and B-cell DLCL cases. Our results suggest that TUNEL-positive cells are not caspase-3-positive and that there is no correlation between DLCL cases with a high degree of DNA fragmentation and caspase-3 immunostaining. Furthermore, a survival curve indicated that a high TUNEL positivity was associated with a poor survival probability (P < 0.02) and a poor response to treatment (P = 0.04). These results confirm the dynamic nature of caspase-3 expression in DLCL and suggests that the pattern of expression of the enzyme has prognostic significance.

Adolescent↗
PubMed1999

The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.

OBJECTIVE: To determine the effect of humanized monoclonal antibody against alpha4 integrin (reactive with alpha4beta1 integrin or very-late antigen-4) on MRI lesion activity in MS. METHODS: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-alpha4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. RESULTS: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. CONCLUSIONS: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

Adult↗
PubMed1999

Nutrition of captive reptiles.

In reptile practice, most nutritional problems arise from improper husbandry, including poor feeding management and provision of imbalanced diets. Each reptile species has its own requirements for temperature and humidity, space and social interaction, lighting, and habitat components. Failure, to provide these requirements often results in failure to thrive and secondary nutritional disorders. Common dietary problems include deficiencies of energy, calcium, vitamin D3, vitamin A, and fiber.

Animal Diseases↗
PubMed1998

Associations between body condition and disease in cats.

OBJECTIVE: To determine the association between body condition and disease in cats. DESIGN: Prospective study. SAMPLE POPULATION: Information on 1,457 cats without major illnesses from 27 veterinary hospitals in the northeastern United States. PROCEDURE: Cats that had body conditions determined from 1991 to 1992, using a set of 6 body condition silhouettes, had their health experiences and body conditions assessed for the subsequent 4.5 years. Cats were described by the following 6 body conditions: cachectic, lean, optimally lean, optimal weight, heavy, and obese. Data obtained from medical records and owner interviews were collected, using standard forms. Associations between body condition and specific diseases were analyzed. Findings in cats with body conditions other than optimal were compared with findings in cats with optimal body condition. RESULTS: Compared with optimal weight cats, heavy cats were 2.9 times as likely to be taken to veterinarians because of lameness not associated with cat bite abscesses. Obese cats were also 3.9 times as likely to develop diabetes mellitus, 2.3 times as likely to develop nonallergic skin conditions, and 4.9 times as likely to develop lameness requiring veterinary care. Cats considered thin (cachectic and lean) were 1.7 times as likely to be presented to veterinary hospitals for diarrhea. CLINICAL IMPLICATIONS: Results of this study substantiate reports of health risks associated with excess body weight in cats. Efforts to reduce weight in heavy and obese cats can lead to reduced risks of diabetes mellitus, lameness (presumably related to osteoarthritis and soft-tissue injuries), and skin problems unrelated to allergies. Cachectic and lean cats are more likely to have diarrhea that is not associated with a definitive diagnosis.

Animals↗
PubMed1996

Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group.

The effects of troglitazone, a novel thiazolidinedione, in non-insulin-dependent diabetic (NIDDM) patients were studied in a double-blind, parallel-group, placebo-controlled, dose-ranging trial. A total of 330 patients (63% male), mean age 57 years (range 39-72), with two fasting capillary blood glucose values > or = 7 and < or = 15 mmol/l (within 2.5 mmol/l of each other) were randomised to treatment with placebo or troglitazone at doses of 200, 400, 600 or 800 mg once daily, or 200 or 400 mg twice daily, for 12 weeks. Prior to the study, treatment had been with diet alone (38% patients) or with oral hypoglycaemic agents which were stopped 3-4 weeks before study treatment started. During treatment, HbA1c tended to rise in patients taking placebo (7.2-8.0%), but remained unchanged with all doses of troglitazone. After 12 weeks of treatment, HbA1c was significantly lower in the troglitazone-treated (mean 7.0-7.4%) compared to the placebo-treated (8.0%) patients (p = 0.055 to < 0.001), as was fasting serum glucose concentration (troglitazone, 9.3-11.0 mmol/l vs placebo, 12.9 mmol/l, p < 0.001). All doses of troglitazone were equally effective. Troglitazone also lowered fasting plasma insulin concentration, by 12-26% compared to placebo (p = 0.074 to < 0.001). Insulin sensitivity assessed by homeostasis model assessment (HOMA) was greater after 12 weeks of treatment in troglitazone-treated patients (troglitazone, 34.3-42.8% vs placebo, 29.9%, p < 0.05). In addition, serum triglyceride and non-esterified fatty acid concentrations were significantly lower and HDL cholesterol higher at troglitazone doses of 600 and 800 mg/day. LDL cholesterol increased at 400 and 600 mg doses only (from 4.3 and 3.9 mmol/l at baseline to 4.8 and 4.5 mmol/l, respectively at 12 weeks, p < 0.05), but not at doses of 800 mg once daily or 400 mg twice daily. LDL/HDL ratio did not change during treatment. All doses were well tolerated; incidence of adverse events in troglitazone-treated patients was no higher than in those treated with placebo. However, a tendency to reduced neutrophil counts was observed in patients taking the highest doses of troglitazone. We conclude that troglitazone is effective and well-tolerated and shows potential as a new therapeutic agent for the treatment of NIDDM.

Adult↗
PubMed1994

Growth of juvenile green iguanas (Iguana iguana) fed four diets.

Wild green iguanas consume a primarily folivorous diet. As pets in captivity, they suffer high mortality and malnutrition. Nutrient requirements are not established. The purpose of this study was to compare growth in juvenile iguanas fed three commercial diets and a romaine-based diet. Twelve nominally 4-wk-old iguanas were fed in a latin square design each of four diets for 8 wk, consisting of a 2-wk accommodation period and a 6-wk collection period. Diets were analyzed at the beginning and end of the study. Food consumption was measured daily; body weights and lengths were measured weekly. For Diets A, B, C and D mean body weight gains were--3, 6, 31 and 60% in 6 wk, respectively. Gain in body weight and snout-vent length increased linearly with dietary protein and fiber and with dry matter intake. The data suggest that growth in pet green iguanas may achieve rates for farmed and wild green iguanas when diets are palatable and contain adequate protein and fiber.

Animal Feed↗
PubMed1994

Body condition of cats.

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Animal Nutritional Physiological Phenomena↗
PubMed1994

Nutritional support of hospitalised dogs and cats.

Nutritional support of hospitalised dogs and cats improves recovery from illness, reduces mortality, and improves responses to trauma and stress. The primary goal of nutritional support is to prevent use of tissue protein. This is accomplished by the provision of sufficient calories and dietary protein in optimal proportions. For nutritional support, calorie intake is adjusted according to the patient's metabolic rate so that the animal may be fed above or below its usual intake. Nutritional support should always be started gradually, no matter what the final calorie goal may be. For many sick dogs fed enterally, diets proved about 30% of calories from fat and at least 27% of calories from protein. Carbohydrates in nutritional support diets should not include maize, wheat or, especially, soy. Sick cats fed enterally should receive at least 30% of calories from both fat and protein.

Animals↗