PubMed Health⌕ Search

Biomedical subjects

D B Muchmore

Publications and source records attributed to D B Muchmore.

13 recordsLinked to original sources
PubMed2006

Efficacy and safety of preprandial human insulin inhalation powder versus injectable insulin in patients with type 1 diabetes.

AIMS/HYPOTHESIS: The efficacy and safety of human insulin inhalation powder (HIIP) plus insulin glargine were compared to subcutaneously injected insulin (SC insulin) plus insulin glargine in patients with type 1 diabetes. METHODS: This was a randomised, open-label crossover study in which one group of patients received preprandial HIIP plus insulin glargine for 12 weeks, followed by the same duration with preprandial SC insulin (lispro or regular) plus insulin glargine. Another group of patients received the reverse treatment sequence. The trial was designed as a non-inferiority comparison of the two treatments for effect on HbA(1c); blood glucose levels were also monitored. Safety assessments included adverse event reporting and hypoglycaemic events. RESULTS: HbA(1c) at endpoint was 7.95+/-0.12% for the HIIP treatment and 8.06+/-0.12% for the SC insulin treatment; mean changes from baseline to endpoint were -0.08 and 0.00%, respectively, (p=NS). The upper limit of the 95% CI of mean difference in HbA(1c) between the two treatments was 0.02%, indicating that HIIP was not inferior relative to SC insulin, as measured against the pre-defined margin of 0.3%. Fasting blood glucose was significantly lower for HIIP treatment (8.09+/-0.33 mmol/l; n=117) than for SC insulin treatment (9.05+/-0.33 mmol/l; n=111) (p=0.01). Safety profiles were comparable between the two treatments. The rate of any hypoglycaemia (least-squares mean adjusted for 30 days+/-SE) was 8.9+/-0.7 and 8.2+/-0.8 for HIIP and SC insulin treatments, respectively, (p=0.29). The rate of nocturnal hypoglycaemia was greater for HIIP (4.2+/-0.4) than for SC insulin (2.7+/-0.4; p<0.001). CONCLUSIONS/INTERPRETATION: HIIP was similar in efficacy to SC insulin for glycaemic control in type 1 diabetes mellitus. The two treatments had comparable safety profiles.

Administration, Inhalation↗
PubMed2001

Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation.

Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis. This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial. Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board. A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60 mg/day, and 2,572 raloxifene 120 mg/day. Women were a mean of 66.5-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures). As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 0.28, 95% confidence interval (CI) 0.17, 0.46). These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 0.16, 95% CI 0.09, 0.30). Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0.003). We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both. Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer.

Aged↗
PubMed2001

Effect of raloxifene on breast cancer cell Ki67 and apoptosis: a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients.

PURPOSE: Raloxifene is a selective estrogen receptor (ER) modulator approved for prevention and treatment of postmenopausal osteoporosis. This is an exploratory study of raloxifene in primary breast cancer patients. EXPERIMENTAL DESIGN: Postmenopausal women (50-80 years of age), with histological or cytological diagnosis of stage I or II primary breast cancer, were randomly assigned to 14 days of placebo, 60 mg/day raloxifene, or 300 mg twice daily (600 mg/day) of raloxifene. A core biopsy of the primary tumor was obtained before therapy, and a representative sample of the excised tumor was obtained from the operative specimen after treatment. Paired baseline and endpoint biopsies from each patient were analyzed for Ki67, apoptosis, and estrogen and progesterone receptors. Treatment group differences in efficacy measurements were primarily evaluated for baseline-to-endpoint change and percentage change using a one-way ANOVA with treatment as the fixed effect. RESULTS: Of 167 enrolled patients, 143 had evaluable efficacy data. Most breast cancer cases were invasive (98.6%), stage I (76.6%), and ER-positive (83.2%). In patients with ER-positive tumors, Ki67 increased 7% from baseline on placebo and decreased by 21% on 60 mg/day raloxifene (P = 0.015 versus placebo) and by 14% on 600 mg/day raloxifene (P = 0.064 versus placebo). Raloxifene did not affect apoptosis. ER decreased significantly with 60 mg/day or 600 mg/day raloxifene compared with placebo (P < 0.01 for each comparison). Raloxifene had no statistically significant effects on Ki67 among patients with ER-negative tumors. There were no treatment differences in adverse events. CONCLUSION: In this exploratory trial, 60 mg/day raloxifene showed a significant antiproliferative effect in ER-positive breast cancer, demonstrated by the decrease in Ki67, with no effect in ER-negative cancer. This provides support for raloxifene having a breast cancer preventive effect in postmenopausal women.

Adult↗
PubMed2000

A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women.

Raloxifene HCl, a selective estrogen receptor modulator, has been shown to increase bone mineral density (BMD) and decrease biochemical markers of bone turnover in postmenopausal women without stimulatory effects on the breast and uterus. However, it is not known whether the changes in BMD and bone turnover are associated with changes at the tissue level, nor how changes with raloxifene compare with estrogen. In this randomized, double blind study, we evaluated the effects of raloxifene (Evista, 60 mg/day) or conjugated equine estrogens (CEE; Premarin, 0.625 mg/day) on bone architecture, bone turnover, and BMD. Iliac crest bone biopsies were obtained at baseline and at the end of the study after double tetracycline labeling and were analyzed for standard histomorphometric indexes. Serum and urinary biochemical markers of bone turnover were measured at baseline and at 4, 10, 18, and 24 weeks of treatment. Total body, lumbar spine, and hip BMD were measured at baseline and at the end of the study by dual energy x-ray absorptiometry. Activation frequency and bone formation rate/bone volume were significantly decreased from baseline in the CEE, but not in the raloxifene, group. Bone mineralization did not change in either group. Most markers of bone resorption and formation decreased in both groups, but to a greater degree in the CEE group (P < .05). Total body and lumbar spine BMD increased from baseline in both groups, with a greater increase in the CEE group (P < 0.05). Hip BMD significantly increased from baseline in the raloxifene group, but the change was not different from that in the CEE group. These results suggest that raloxifene reduces bone turnover and increases bone density, although to a lesser extent than CEE. Thus, raloxifene is an alternative to CEE for the prevention and treatment of osteoporosis in postmenopausal women.

Aged↗
PubMed2000

Raloxifene: A selective estrogen receptor modulator (SERM) with multiple target system effects.

Selective estrogen receptor modulators (SERMs) exhibit a pharmacologic profile characterized by estrogen agonist activity in some tissues with estrogen antagonist activity in other tissues. These compounds were initially called "antiestrogens," but it was subsequently recognized that this inadequately described their spectrum of activities. The first widely used SERM, tamoxifen, has estrogen antagonist activity in breast tissue but shows estrogen-like activity in other tissues. Raloxifene is another SERM in clinical use, and it was developed to avoid some of the undesirable estrogen agonist actions of other SERMs to improve the drug safety profile. Raloxifene has been introduced for clinical use in treatment and prevention of postmenopausal osteoporosis. This review will explore the preclinical and clinical pharmacology of raloxifene, and compare it to other SERMs currently available for clinical use.

Bone and Bones↗
PubMed1996

Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Glimepiride Study Group.

OBJECTIVE: To compare the efficacy and safety of two daily doses of the new sulfonylurea, glimepiride (Amaryl), each as a once-daily dose or in two divided doses, in patients with NIDDM. RESEARCH DESIGN AND METHODS: Of the previously treated NIDDM patients, 416 entered this multicenter randomized double-blind placebo-controlled fixed-dose study. After a 3-week placebo washout, patients received a 14-week course of placebo or glimepiride 8 mg q.d., 4 mg b.i.d., 16 mg q.d., or 8 mg b.i.d. RESULTS: Fasting plasma glucose (FPG) and HbA1c values were similar at baseline in all treatment groups. The placebo group's FPG value increased from 13.0 mmol/l at baseline to 14.5 mmol/l at the last evaluation endpoint (P < or = 0.001). In contrast, FPG values in the four glimepiride groups decreased from a range of 12.4-12.9 mmol/l at baseline to a range of 8.6-9.8 mmol/l at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change [vs. placebo] from baseline). Two-hour postprandial plasma glucose (PPG) findings were consistent with FPG findings. In the placebo group, the HbA1c value increased from 7.7% at baseline to 9.7% at endpoint (P < or = 0.001), whereas HbA1c values for the glimepiride groups were 7.9-8.1% at baseline and 7.4-7.6% at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change from baseline). There were no meaningful differences in glycemic variables between daily doses of 8 and 16 mg or between once- and twice-daily dosing. Adverse events and laboratory data demonstrate that glimepiride has a favorable safety profile. CONCLUSIONS: Glimepiride is an effective and well-tolerated oral glucose-lowering agent. The results of this study demonstrate maximum effectiveness can be achieved with 8 mg q.d. of glimepiride in NIDDM subjects.

Blood Glucose↗
PubMed1994

Self-monitoring of blood glucose in overweight type 2 diabetic patients.

Self-monitoring of blood glucose (SBGM) is widely recommended for both type 1 and type 2 diabetic patients despite the lack of evidence of benefit in glucose control or as an aid in weight loss in type 2 subjects. This study tested the hypothesis that combined use of SMBG and dietary carbohydrate (CHO) counting, using the blood monitoring results to shape dietary CHO quotas, is beneficial in managing type 2 diabetes. Twenty-three overweight (body mass index, BMI 27.5-44 kg/m2) patients aged 40-75 participated in a 28-week behavioral weight control program. Baseline hemoglobin HbA1c ranged between 9.5% and 13.5% (normal range 5.5%-7.7%). Subjects were matched for weight, sex, and HbA1c and assigned to small (4-8 participants) groups which met weekly for 12 weeks and then monthly for 16 weeks. After 8 weeks, the groups were randomized either to continue the behavioral program or to have SMBG and dietary CHO counting. Glucose monitoring was performed 6 times daily (pre- and 2 h postprandially) for the first month, focusing on the meal increment and correlating this to dietary CHO intake. Weight loss was identical in both groups during the year of follow-up. The HbA1c level showed a progressive decline in experimental subjects (P < 0.05), whereas there was no improvement in control subjects.

Adult↗
PubMed1992

Do estrogens improve bone mineral density in osteoporotic women over age 65?

A retrospective analysis of our experience with estrogen and fluoride treatment in 91 patients with postmenopausal osteopenia followed for 6-47 months has been performed. Treatment included calcium (1000 mg/day) and either conjugated estrogens (0.625 mg/day) or sodium fluoride (50 mg/day), or both. All patients had at least two serial dual-photon spinal bone mineral density measurements performed 6 months or more apart. Estrogen treatment was associated with increased bone mineral density (5.3%/year), as was fluoride alone (7.5%/year). Estrogen and fluoride together were additive (9.6%/year). In women over age 65 the estrogen effect was just as great (6.9%/year) as in younger women. Estrogen benefit occurred predominantly in the first 18 months of treatment (7.0%/year), after which time changes in bone mineral density were similar to those in untreated controls, who showed stable bone mineral density. We conclude that aggressive estrogen and fluoride treatment tailored to the severity of the individual's postmenopausal osteopenia results in short-term improvement in spinal bone mineral density. These data further support that elderly women respond to estrogen replacement therapy with absolute and relative increments in bone density similar to those in younger women.

Absorptiometry, Photon↗
PubMed1983

Glycogen synthesis stimulation by adenylate cyclase inhibition in rat epididymal adipocytes.

The effects of adenylate cyclase inhibition on the transport of glucose and fructose and their incorporation into glycogen were investigated in order to assess the extent to which lowered cAMP levels can take part in the various components of glycogen synthesis regulation in isolated rat epididymal adipocytes. The dose-response characteristics of (R)-N-(2-phenylisopropyl)adenosine (PIA), a potent and specific adenylate cyclase inhibitor, on glycogen synthesis were compared with those effectively inhibiting lipolysis, a measure of functional cAMP levels. PIA had no effect on basal glucose or fructose transport but stimulated glucose and fructose incorporation into glycogen. Their respective incorporation was 10 and 69% of that achieved in the presence of insulin. These effects of PIA were shown to be in part the result of increased glycogen synthase I activity. PIA was 20% as effective as insulin in this action. Thus, were insulin to lower cAMP levels and/or inhibit cAMP-dependent protein kinase, this action would be irrelevant to glucose transport but would contribute to the stimulation of glycogen metabolism. However, an additional mechanism(s) involving neither increased glucose transport nor lowered cAMP levels is required to account for the full action of insulin. Fat cells in the absence of medium glucose and in the presence of 10(-7) M PIA and adenosine deaminase constitute a system functionally depleted of cAMP where this mechanism can be studied in isolation.

Adenosine↗
PubMed1982

On the mechanisms of inhibition of insulin action by small-molecular-weight trypsin inhibitors.

Evidence from a number of laboratories has suggested that the mechanism of insulin action involves the release of an intracellular mediator polypeptide from the plasma membrane. It has been proposed that activation of a protease with trypsin-like specificity is involved in release of the putative mediator. In an effort to assess the potential role of such a protease in intact cells, the present study tested the effects of a variety of low-mol-wt protease inhibitors on insulin's metabolic action in isolated rat epididymal fat cells. The protease inhibitors studied included p-aminobenzamidine, benzamidine, phenylguanidine, diisopropylfluorophosphate, leupeptin, and the competitive substrate N-alpha-tosyl-L-arginine methylester. Leupeptin was devoid of activity. Most of the other inhibitors used were able to interfere with insulin-stimulated metabolism if used in sufficiently high concentrations, concentrations considerably higher than those required for inhibition of known proteases or inhibition of intracellular processes in a previously described system which involves a trypsin-like enzyme. Moreover, they displayed various activities unrelated to protease inhibition that could explain their effects on insulin action better than protease inhibition. While none of the data on individual inhibitors were by themselves convincing enough to either confirm or reject the hypothesis concerning the involvement of a protease with trypsin-like specificity in insulin action, taken together our results do weaken the hypothesis considerably and in particular render the involvement of an extracellular trypsin-like enzyme improbable.

Adipose Tissue↗