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Biomedical subjects

M Greenwald

Publications and source records attributed to M Greenwald.

At least 19 recordsLinked to original sources
PubMed2005

Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study.

BACKGROUND: Reducing bisphosphonate dosing frequency may improve suboptimal adherence to treatment and therefore therapeutic outcomes in postmenopausal osteoporosis. Once-monthly oral ibandronate has been developed to overcome this problem. OBJECTIVE: To confirm the 1 year results and provide more extensive safety and tolerability information for once-monthly dosing by a 2 year analysis. METHODS: MOBILE, a randomised, phase III, non-inferiority study, compared the efficacy and safety of once-monthly ibandronate with daily ibandronate, which has previously been shown to reduce vertebral fracture risk in comparison with placebo. RESULTS: 1609 postmenopausal women were randomised. Substantial increases in lumbar spine bone mineral density (BMD) were seen in all treatment arms: 5.0%, 5.3%, 5.6%, and 6.6% in the daily and once-monthly groups (50 + 50 mg, 100 mg, and 150 mg), respectively. It was confirmed that all once-monthly regimens were at least as effective as daily treatment, and in addition, 150 mg was found to be better (p<0.001). Substantial increases in proximal femur (total hip, femoral neck, trochanter) BMD were seen; 150 mg produced the most pronounced effect (p<0.05 versus daily treatment). Independent of the regimen, most participants (70.5-93.5%) achieved increases above baseline in lumbar spine or total hip BMD, or both. Pronounced decreases in the biochemical marker of bone resorption, sCTX, observed in all arms after 3 months, were maintained throughout. The 150 mg regimen consistently produced greater increases in BMD and sCTX suppression than the 100 mg and daily regimens. Ibandronate was well tolerated, with a similar incidence of adverse events across groups. CONCLUSIONS: Once-monthly oral ibandronate is at least as effective and well tolerated as daily treatment. Once-monthly administration may be more convenient for patients and improve therapeutic adherence, thereby optimising outcomes.

Administration, Oral↗
PubMed2003

The prediction of individual differences in response to D-amphetamine in healthy adults.

Based on previous animal work, the present study investigated whether individual differences in motor activity in a novel environment predicted reinforcing and behaviorally activating effects of D-amphetamine (0, 5, 10 and 20 mg p.o.) in healthy adults. When exposed to a novel environment, 18 participants had high levels of motor activity (high responders; HR) and six had low levels (low responders; LR). These group differences were used to predict effects of D-amphetamine on drug reinforcement, salivary cortisol, motor activity, subjective effects, and acoustic startle reflex in subsequent sessions. Unlike observations in rodents, (1). dose-dependent reinforcing effects of D-amphetamine were evident but without group differences; (2). motor activity was greater in HR but did not vary with D-amphetamine dose; and (3). cortisol levels were not related to the reinforcing effects of D-amphetamine. Startle reflex amplitudes were greater in HR following placebo, but D-amphetamine 20 mg equalized this group difference. There was a trend towards less prepulse inhibition of the acoustic startle reflex in HR compared to LR. LR reported greater overall negative effect following amphetamine administration, but this was not consistently related to dose. Finally, participants with high sensation-seeking personality scores exhibited less prepulse inhibition. The results are discussed in terms of the extant literature.

Adult↗
PubMed2001

Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila.

Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms.

Acetylation↗
PubMed2001

A multicenter, randomized, controlled trial to evaluate the safety profile, tolerability, and efficacy of rofecoxib in advanced elderly patients with osteoarthritis.

This 6-week study was conducted to test the efficacy, safety, and tolerability of rofecoxib (a selective COX-2 inhibitor) compared to nabumetone (a non-selective NSAID) and placebo in osteoarthritis (OA) patients aged 80 and older. Three hundred forty-one patients, mean age 83 years, were randomized. Allocations were made in an approximately 1:2:1:2 ratio (placebo: 12.5 mg rofecoxib: 25 mg rofecoxib: 1500 mg nabumetone). Least square mean changes from baseline in the primary efficacy endpoint, Patient Global Assessment of Disease Status, were as follows (with negative numbers indicating improvement): -14.85 mm for placebo; -25.34 mm for 12.5 mg rofecoxib; -25.40 mm for 25 mg of rofecoxib; and -25.95 mm for nabumetone (p<0.001 for all active treatments vs placebo.) Results from secondary endpoints, including the 3 WOMAC sub-scales (pain, stiffness, and disability) and the Investigator Global Assessment of Disease Status, were consistent with those for the primary endpoint. No significant between-group differences were observed in the proportions of patients who discontinued treatment due to either clinical or laboratory adverse experiences. Renal safety (edema and hypertension adverse experiences) was similar for rofecoxib and nabumetone. No gastroduodenal ulcers occurred; however, the demonstration of gastrointestinal risk with rofecoxib or nabumetone was beyond the scope of this trial. We conclude that in patients 80 years and older, rofecoxib, 12.5 mg and 25 mg once daily, demonstrated clinical efficacy for the treatment for OA as did 1500 mg of nabumetone. Rofecoxib and nabumetone were generally well tolerated in this elderly population.

Aged↗
PubMed2001

Pseudotumor of the bladder as a manifestation of uncomplicated appendicitis.

We report the case of a 67-year-old woman who presented with an apparent bladder tumor and complaints of increased urinary frequency and postvoiding pain. Her diagnostic work-up revealed conflicting findings regarding the source of her bladder disease, and laparoscopy was required to make the final diagnosis of appendicitis. The presentation of appendicitis can be disguised and is often a difficult diagnosis.

Aged↗
PubMed2000

The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.

Huntington's Disease (HD) is caused by an expansion of a polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequences to nuclear function of a pathogenic amino-terminal region of htt (httex1p) including aggregation, protein-protein interactions, and transcription. httex1p was found to coaggregate with p53 in inclusions generated in cell culture and to interact with p53 in vitro and in cell culture. Expanded httex1p represses transcription of the p53-regulated promoters, p21(WAF1/CIP1) and MDR-1. httex1p was also found to interact in vitro with CREB-binding protein (CBP) and mSin3a, and CBP to localize to neuronal intranuclear inclusions in a transgenic mouse model of HD. These results raise the possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD.

Animals↗
PubMed2000

From homoleptic to heteroleptic double stranded Copper(I) helicates: the role of self-recognition in self-assembly processes

The ligands 2,9-bis[(6-methyl-2, 2'-bipyridin-6'-yl)methyleneoxymethylenyl]-1,10-phenanthroline (6), 6' ',6' "-bis[(6-methyl-2, 2'-bipyridin-6'-yl)methyleneoxymethylenyl)]-2' ',2' "-bipyridine (2), 5,5'-bis[(6-methyl-2,2'-bipyridin-6'yl)methyleneoxymethylenyl]-2, 2'-bithiophene (7), and 6,6'-bis[(6-methyl-2, 2'-bipyridin-6'-yl)methyleneoxymethylenyl]-2,2'-biphenyl (8) and their respective homo- and heteroleptic double-stranded copper(I) complexes were prepared and characterized in order to estimate the importance of self-recognition in the self-assembly processes of double-stranded copper complexes. The homoleptic double-stranded copper complexes of 2, 6, 7, and 8 were characterized by NMR, FAB-MS, and electrochemistry. It was found that 6 and 2 each form a single double-stranded helicate having the structure of [(L)(2)Cu(3)](3+) (L = 2 or 6), 7 forms two double-stranded [(7)(2)Cu(3)](3+) complexes, and 8 results in a mixture of at least two [(8)(2)Cu(2)](2+) complexes. The potential shift, DeltaE degrees (,) of the Cu(+)/Cu(2+) redox process of these complexes reflects the binding affinity of the different binding sites to the copper cation. The electrochemical data show that the central units have a higher affinity to Cu(+) as compared to the off-center binding sites. NMR was used to determine the actual complex composition obtained from different mixtures of 2, 6, or 7 with Cu(+). Interestingly, we have found that, although 6, 2, and 7 each form homoleptic double-stranded complexes, no heteroleptic double-stranded copper complexes were formed from the mixtures of 7 with either 6 or 2. However, when mixtures of 6 and 2 are used, helicate distributions seem to follow simple statistics. These results are discussed in terms of the relative importance of self-recognition in the self-assembly of double-stranded helicates.

Journal Article↗
PubMed2000

An estradiol matrix transdermal system for the prevention of postmenopausal bone loss.

OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and tolerability of 2 years' application of an estradiol matrix transdermal system for the prevention of postmenopausal bone loss. METHODS: In this multicenter, randomized, placebo-controlled, parallel-group study, 261 surgically or naturally postmenopausal women were randomized to apply the estradiol matrix transdermal system (0.025, 0.0375, 0.05, or 0.1 mg/d) or matching placebo twice a week for 2 years. The study was double blind with respect to treatment (active vs placebo) but not to the dose levels of active treatment (because of the differing sizes and shapes of the patches). In addition to receiving the assigned treatment, the 100 nonhysterectomized women received 2.5 mg medroxyprogesterone acetate daily throughout the study. RESULTS: The evaluable group (n = 259) had a mean age of 52 years and a mean duration of menopause of 32 months. Following 2 years of treatment, there were significant differences in favor of estradiol between all doses of the estradiol matrix transdermal system and placebo in terms of the percentage change from baseline in the bone mineral density (BMD) of the L1-L4 anteroposterior lumbar spine (0.1 and 0.05 mg/d, P < 0.001; 0.0375 mg/d, P = 0.024; 0.025 mg/d, P = 0.002). Percentage changes from baseline in the BMD of the femoral neck after 2 years of treatment also consistently demonstrated the efficacy of the estradiol matrix transdermal system compared with placebo (all, P < or = 0.044). The estradiol matrix transdermal system was well tolerated. CONCLUSION: The estradiol matrix transdermal system was effective in preventing postmenopausal bone loss at dosages of 0.025 to 0.1 mg/d, and had a safety profile consistent with the known effects of estrogen/progestin.

Administration, Cutaneous↗
PubMed1999

Relative cytotoxic activity of immunotoxins reactive with different epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185.

Different epitopes on the extracellular domain of the HER-2 receptor can serve as distinct targets for immunotoxins. To determine the optimal epitope target for immunotoxin therapy, 7 anti-HER-2 ricin A chain murine monoclonal immunotoxins, each reactive with different epitopes of HER-2 receptor, were tested for cytotoxic activity. The immunotoxins produced 1.2-4.6 logs of cytotoxicity in limiting dilution clonogenic assays with 2 breast cancer cell lines that overexpressed HER-2. Cytotoxicity did not correlate with immunoglobulin isotype, binding affinity, relative position of epitopes or internalization of the anti-HER-2 immunotoxins. Interestingly, the most and least effective immunotoxins bound to epitopes in very close proximity. Competitive binding assays with unconjugated antibodies have previously indicated that our antibodies recognized epitopes that are arranged in a linear array. To orient this relative epitope map, deletions were prepared in the HER-2/neu gene and these mutant constructs were expressed in NIH3T3 cells. Epitope expression was determined by antibody binding and radioimmunoassay. Epitopes targeted by the PB3, 454C11 and NB3 antibodies are localized N-terminal to the epitopes recognized by ID5, BD5, 741F8 and 520C9 antibodies. The 2 non-conformational epitopes PB3 and NB3 were localized to regions corresponding to amino acides 78-242 of the p185(HER-2) protein.

3T3 Cells↗
PubMed1999

Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: Risedronate, a new pyridinyl bisphosphonate, is a potent antiresorptive bone agent. This study examines the safety and efficacy of daily, oral risedronate therapy for the prevention of corticosteroid-induced bone loss. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 224 men and women who were initiating long-term corticosteroid treatment. Patients received either risedronate (2.5 mg or 5 mg) or placebo daily for 12 months. Each patient also received 500 mg of elemental calcium daily. The primary outcome measure was the percentage of change in lumbar spine bone mineral density (BMD). Secondary measures included proximal femur BMD and incidence of vertebral fractures. RESULTS: After 12 months, the lumbar spine BMD (mean +/- SEM) did not change significantly compared with baseline in the 5-mg (0.6 +/- 0.5%) or the 2.5-mg (-0.1 +/- 0.7%) risedronate groups, while it decreased in the placebo group (-2.8 +/- 0.5%; P < 0.05). The mean differences in BMD between the 5-mg risedronate and the placebo groups were 3.8 +/- 0.8% at the lumbar spine (P < 0.001), 4.1 +/- 1.0% at the femoral neck (P < 0.001), and 4.6 +/- 0.8% at the femoral trochanter (P < 0.001). A trend toward a decrease in the incidence of vertebral fracture was observed in the 5-mg risedronate group compared with the placebo group (5.7% versus 17.3%; P = 0.072). Risedronate was well tolerated, and the incidence of upper gastrointestinal adverse events was comparable among the 3 groups. CONCLUSION: Risedronate therapy prevents bone loss in patients initiating long-term corticosteroid treatment.

Adolescent↗
PubMed1998

Pharmacokinetic predisposition to nicotine from environmental tobacco smoke: a risk factor for pediatric asthma.

During the last decade several studies have shown that children whose parents smoke have higher rates of asthma. Recently, hair concentrations of cotinine have been shown to reflect systemic exposure to this constituent of smoke in both children and adults. At the present time it is not known, however, why some children exposed to passive smoking have asthma while others, similarly exposed, do not. The present study aimed at verifying whether asthmatic children are different from nonasthmatic children exposed to similar degrees of passive smoking in the way their bodies handle nicotine, a constituent of cigarette smoke. Seventy-eight asthmatic children were compared to 86 control children, all attending a consulting pediatric clinic in Toronto. A questionnaire completed by the parents and children detailed the daily number of cigarettes the child was exposed to and the identity of the smokers. Clinical data were extracted from the patients' charts. Urinary (corrected for creatinine) and hair concentrations of cotinine were measured by radioimmunoassays. The asthmatic and control children were of similar age, gender, and ethnic distribution, parental education, and socioeconomic status. Parents of asthmatic children tended to report a lower daily number of cigarettes (7.4 +/- 1.3/day vs. 11.2 +/- 2.3/day, p = 0.14), and this report agreed with the trend of urinary cotinine (47.1 +/- 9.1 ng/mg vs. 62.6 +/- 11.5 ng/mg, respectively). Conversely, children with asthma had on average twofold higher concentrations of cotinine in their hair (0.696 +/- 0.742 ng/mg) than control children (0.386 +/- 0.383) (p = 0.0001). In a similar manner, the hair:urine concentration ratio was significantly higher in children with asthma (0.028 +/- 0.002) than in their controls (0.18 +/- 0.003) (p = 0.0001). These results suggest that under exposure to similar amounts of nicotine, children with asthma have on average twofold higher systemic exposure to this constituent of cigarette smoke. These data suggest that out of all children passively exposed to environmental tobacco smoke, those who exhibit asthma have a higher systemic exposure to nicotine, possibly due to lower clearance rate. This is the first evidence of pharmacokinetic predisposition to environmental tobacco smoke as an etiological factor in pediatric asthma.

Adult↗
PubMed1997

Effect of bone density information on decisions about hormone replacement therapy: a randomized trial.

OBJECTIVE: To determine the effect of bone density information on a woman's decision about hormone replacement therapy (HRT). METHODS: One hundred forty women were assigned randomly to receive either educational information about osteoporosis and a voucher for a bone mineral density test 12 months later or the same educational information plus an immediate dual-energy x-ray absorptiometry test for bone mineral density. Women in both groups were offered prescription for HRT. RESULTS: Of the 93 women who received a bone mineral density test, 63.4% elected HRT and filled their prescription, compared with only 20.0% of the 43 women who did not have a bone mineral density test (P < .01). Women who were classified as osteopenic (between -1 and -2.5 standard deviations [SDs] of the young normal bone mineral density) or osteoporotic (more than 2.5 SDs below young normals) were more likely to choose HRT (69.4%) than were women whose bone mineral density was in the normal range (51.6%) (above -1 SD of the young normal bone mineral density value). CONCLUSIONS: A bone mineral density test, regardless of the result, had a significant effect on women's decisions to accept HRT. Within the group having the test, women with lower bone mineral density were more likely to choose HRT.

Absorptiometry, Photon↗
PubMed1996

Syncytium formation by recombinant HTLV-II envelope glycoprotein.

Infection by human T-cell leukemia viruses (HTLV-I and HTLV-II) induces syncytium formation in certain cell types in vitro. Recombinant vaccinia viruses expressing the HTLV-II envelope (Env) gp61-II were used to infect human cells, and syncytium formation was observed, demonstrating that HTLV-II Env expression was sufficient to mediate syncytium formation in appropriate cells. This syncytium formation could be blocked by sera from HTLV-II-infected individuals. Infection with these recombinant vaccinia viruses caused fusion in mouse/human hybrid cells containing only human chromosome 17, whereas there was no obvious syncytium formation in mouse cells. This fusogenic phenotype of recombinant gp61-II is likely a property of the specific interaction between HTLV-II envelope protein and the HTLV cellular receptor, encoded by a gene that was previously indicated to be on human chromosome 17. On this basis, we developed a sensitive syncytium formation assay, using lacZ gene activation, for detecting the presence of the HTLV receptor(s). We used this fusion assay to test for HTLV receptor activity on a variety of cells. Our findings indicate that the HTLV receptor is widely distributed among species and cell types, including, to a limited extent, murine cells.

Animals↗
PubMed1996

Passive smoking in children. Racial differences in systemic exposure to cotinine by hair and urine analysis.

Passive smoking has been shown to adversely affect the health of infants and children. Black children and adults appear to be more susceptible to a variety of tobacco smoke health hazards for unknown reason. The objectives of this study were as follows: (1) to correlate the number of cigarettes reported to have been smoked by parents with urine and hair concentrations of cotinine in children; and (2) to identify race differences in systemic exposure to cotinine in children. This was an observational study in a consulting pediatric office on 169 nonsmoking children between 2 and 18 years of age, not actively smoking. The outcome measures of interest were urinary cotinine concentrations corrected for milligram of creatinine and hair concentration of cotinine (per milligram of hair). There were significant correlations between the number of cigarettes the child was exposed to and urinary cotinine (r = 0.68, p = 0.0001) or hair cotinine concentrations (r = 0.19, p = 0.02), and between urinary and hair cotinine (r = 0.3, p = 0.0005). In this cohort, parents of black children (n = 21) tended to smoke less (6.6 +/- 3/d, mean +/- SEM) than white parents (n = 97) (12 +/- 1.8, mean +/- SEM) (p = 0.2). Despite being exposed to less cigarettes, black children had higher hair concentrations of cotinine than white children (0.89 +/- 0.25 ng/mg vs 0.48 +/- 0.05 ng/mg; p = 0.05). The ratio hair/urine concentrations of cotinine was twofold higher in black children (0.035 +/- 0.01 vs 0.019 +/- 0.002; p = 0.004). White children with dark hair did not differ significantly from white children with fair hair in any of these indexes. The amount of urinary cotinine per milligram of creatinine caused by 1 cigarette per day was twofold higher in black children (14.7 +/- 5.2 ng/mg of creatinine) than in white children (6.3 +/- 1.2 ng/mg of creatinine) (p = 0.02). These data suggest that black children handle cigarette smoke differently from white children and that black children have higher systemic exposure to this constituent of cigarette smoke.

Adolescent↗
PubMed1996

Use of astemizole in a large group practice.

Astemizole was released in 1988. In late 1992, a new warning label was added in response to reports of syncope and death from arrhythmia. Records of patients given new prescriptions for astemizole were reviewed to assess compliance with the warnings in a large multispecialty practice. The indication was appropriate in 89% of cases. Excessive doses were used in 4% of cases. Two percent of prescriptions were given to patients with contraindications. Only two complications were documented. Despite carrying a drug warning, astemizole continues to be used inappropriately and is a medicolegal concern. Education and drug evaluations can be used to enhance compliance and decrease the risk associated with the use of astemizole.

Arrhythmias, Cardiac↗