Effects of saxagliptin on ß-cell stimulation and insulin secretion in patients with type 2 diabetes.

AIM: To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on ß-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. METHODS: Patients in this randomized, parallel-group, double-blind, placebo-controlled study were drug-naïve, aged 43-69 years, with baseline haemoglobin A1c (HbA1c) 5.9-8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0-180 min, fasting state), and intravenous-oral hyperglycaemic clamp (180-480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. RESULTS: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference -21.8% vs. placebo, p = 0.03). CONCLUSIONS: DPP-4 inhibition with saxagliptin improves pancreatic ß-cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP-4 inhibition on the ß-cell is warranted.

Adrenergic blood pressure responses in the shark.

Both nurse and lemon sharks recovered slowly from the pressor effect of epinephrine and from the depressor effect of isoproterenol. The recovery time increased with the dose of epinephrine. Grading of dosage and the use of dibenzyline revealed that these species exhibit alpha and beta adrenergic vascular responses in a manner qualitatively similar but quantitatively dissimilar to that for mammals.

Addition of biphasic insulin aspart 30 to optimized metformin and pioglitazone treatment of type 2 diabetes mellitus: The ACTION Study (Achieving Control Through Insulin plus Oral ageNts).

AIM: Efficacy and safety of biphasic insulin aspart (BIAsp 30, 30% short-acting and 70% intermediate-acting insulin aspart) added to an optimized treatment of metformin and pioglitazone (met/pio) were compared with treatment with optimized met/pio in type 2 diabetes patients. METHODS: This randomized, 34-week, parallel-group study enrolled insulin-naive, type 2 diabetes patients (HbA(1c) 7.5-12.0%) previously using two oral antidiabetic (OAD) agents. During an 8-week run-in period, treatment was changed to met/pio and doses were adjusted up to 2500 mg/day and 30 or 45 mg/day respectively. Subjects either continued met/pio alone or added BIAsp 30 initiated at 6 units twice daily and titrated to target plasma glucose (PG) (4.4-6.1 mmol/l). RESULTS: At end-of-study, subjects treated with BIAsp 30+met/pio (n = 93) had a mean (+/-s.d.) HbA(1c) reduction significantly greater than treatment with met/pio (n = 88) (1.5% +/- 1.1 vs. 0.2% +/- 0.9, p < 0.0001 between groups). Subjects treated with BIAsp 30+met/pio were more likely to reach The American Association of Clinical Endocrinologists and European Association for the Study of Diabetes/American Diabetes Association HbA(1c) targets of < or =6.5 and <7.0%, respectively, than with met/pio only (HbA(1c)< or =6.5%: 59 vs. 12%; HbA(1c) <7.0%: 76 vs. 24%). At end-of-study, self-monitored glucose profile values at all eight daily time points were significantly less for the BIAsp 30+met/pio group compared with the met/pio group, and minor hypoglycaemia (defined as PG < 3.1 mmol/l) was more frequent (8.3 vs. 0.1 events/year, p < 0.001). Both groups gained weight during treatment (BIAsp 30+met/pio, 4.6 +/- 4.3 kg; met/pio, 0.8 +/- 3.2 kg; p < 0.001). CONCLUSION: Addition of insulin in type 2 patients treated with met/pio is an effective way to achieve glycaemic targets. Treatment with BIAsp 30+met/pio achieved significantly greater reduction in HbA(1c), as compared with met/pio alone. In patients with type 2 diabetes poorly controlled by 2 OADs, more achieved glycaemic targets using BIAsp 30+met/pio than using met/pio alone.

The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus.

AIM: To determine the efficacy and tolerability of PHX1149, a novel dipeptidyl peptidase-4 (DPP4) inhibitor, in patients with type 2 diabetes. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled, 4-week study in patients with type 2 diabetes with suboptimal metabolic control. Patients with a baseline haemoglobin A(1c) (HbA(1c)) of 7.3 to 11.0% were randomized 1 : 1 : 1 : 1 to receive once-daily oral therapy with either PHX1149 (100, 200 or 400 mg) or placebo; patients were on a constant background therapy of either metformin alone or metformin plus a glitazone. RESULTS: Treatment with 100, 200 or 400 mg of PHX1149 significantly decreased postprandial glucose area under the curve AUC(0-2 h) by approximately 20% (+0.11 +/- 0.50, -2.08 +/- 0.51, -1.73 +/- 0.49 and -1.88 +/- 0.48 mmol/l x h, respectively, for placebo and 100, 200 and 400 mg (p = 0.002, 0.008 and 0.004 vs. placebo). Postprandial AUC(0-2 h) of intact glucagon-like peptide-1, the principal mediator of the biological effects of DPP4 inhibitors, was increased by 3.90 +/- 2.83, 11.63 +/- 2.86, 16.42 +/- 2.72 and 15.75 +/- 2.71 pmol/l x h, respectively, for placebo and 100, 200 and 400 mg (p = 0.053, 0.001 and 0.002 vs. placebo). Mean HbA(1c) was lower in all dose groups; the placebo-corrected change in the groups receiving 400 mg PHX1149 was -0.28% (p = 0.02). DPP4 inhibition on day 28 was 53, 73 and 78% at 24 h postdose in the groups receiving 100, 200 and 400 mg PHX1149, respectively. There were no differences in adverse events between PHX1149-treated and placebo subjects. CONCLUSIONS: Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.

Chronic consumption of rebaudioside A, a steviol glycoside, in men and women with type 2 diabetes mellitus.

This trial evaluated the effects of 16 weeks of consumption of 1000mg rebaudioside A (n=60) a steviol glycoside with potential use as a sweetener, compared to placebo (n=62) in men and women (33-75 years of age) with type 2 diabetes mellitus. Mean+/-standard error changes in glycosylated hemoglobin levels did not differ significantly between the rebaudioside A (0.11+/-0.06%) and placebo (0.09+/-0.05%; p=0.355) groups. Changes from baseline for rebaudioside A and placebo, respectively, in fasting glucose (7.5+/-3.7mg/dL and 11.2+/-4.5mg/dL), insulin (1.0+/-0.64microU/mL and 3.3+/-1.5microU/mL), and C-peptide (0.13+/-0.09ng/mL and 0.42+/-0.14ng/mL) did not differ significantly (p>0.05 for all). Assessments of changes in blood pressure, body weight, and fasting lipids indicated no differences by treatment. Rebaudioside A was well-tolerated, and records of hypoglycemic episodes showed no excess vs. placebo. These results suggest that chronic use of 1000mg rebaudioside A does not alter glucose homeostasis or blood pressure in individuals with type 2 diabetes mellitus.

The hemodynamic effects of rebaudioside A in healthy adults with normal and low-normal blood pressure.

Rebaudioside A and stevioside are steviol glycosides extracted from the plant Stevia rebaudiana Bertoni and are used in several countries as food and beverage sweeteners. This randomized, double-blind trial evaluated the hemodynamic effects of 4weeks consumption of 1000mg/day rebaudioside A vs. placebo in 100 individuals with normal and low-normal systolic blood pressure (SBP) and diastolic blood pressure (DBP). Subjects were predominantly female (76%, rebaudioside A and 82%, placebo) with a mean age of approximately 41 (range 18-73) years. At baseline, mean resting, seated SBP/DBP was 110.0/70.3mmHg and 110.7/71.2mmHg for the rebaudioside A and placebo groups, respectively. Compared with placebo, rebaudioside A did not significantly alter resting, seated SBP, DBP, mean arterial pressure (MAP), heart rate (HR) or 24-h ambulatory blood pressures responses. These results indicate that consumption of as much as 1000mg/day of rebaudioside A produced no clinically important changes in blood pressure in healthy adults with normal and low-normal blood pressure.

Pinocytosis by human alveolar macrophages. Comparison of smokers and nonsmokers.

Alveolar macrophages were obtained from human volunteers, smokers and nonsmokers, by bronchial lavage through a fiberoptic bronchoscope. Cells were incubated in a chemically defined medium containing [(14)C]sucrose (0.36 mM) and varying concentrations of rabbit serum. Pinocytosis was assessed by the cellular uptake of isotope over 30, 75, and 120-min periods. Pinocytic activity of smokers' cells was dependent on serum concentration but always less than the activity of nonsmokers' cells. The degree of pinocytosis by nonsmokers' cells was independent of serum concentration. It is concluded that the decreased level of pinocytic activity in smokers' alveolar macrophages as indicated by the uptake of sucrose in the presence of rabbit serum may represent a form of reticuloendothelial blockade.

Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients.

Data from studies in diabetic rodents and evidence from clinical situations of severe resistance to insulin suggest that insulin-like growth factor I (IGF-I) is able to at least partly overcome insulin resistance. To assess the efficacy of recombinant human IGF-I in subjects with the most common form of insulin resistance, e.g., obese, type II diabetic patients, we administered recombinant human IGF-I (rhIGF) in doses of 120 and 160 micrograms/kg twice daily for 4-52 days to seven such individuals who had been treated previously with high doses of insulin (> 0.7 U.kg-1 x day-1). Four patients exhibited comparable or enhanced, whereas three had diminished, blood glucose control on rhIGF-I relative to that while on twice daily NPH insulin during the six-week control period. The occurrence of adverse effects in all patients compelled us to discontinue rhIGF-I administration before completing the 8-week treatment period. These adverse effects included edema primarily on the face and hands, mild weight gain, occasional dyspnea, bilateral jaw tenderness, arthralgias and myalgias, fatigue, tachycardia, flushing, orthostatic hypotension, and local burning at the injection site. We conclude that the frequency and severity of side effects associated with administering high-dose subcutaneous rhIGF-I to obese insulin-resistant diabetic patients make it an unacceptable therapeutic agent for these patients despite its ability to produce reasonable blood glucose control in approximately 50% of them.

Delineation of extended lengths of coronary arteries by multiplane transesophageal echocardiography.

OBJECTIVES: The purpose of this study was to evaluate the utility of multiplane transesophageal echocardiography in assessing the coronary artery tree. BACKGROUND: Evaluation of coronary disease with single-plane and biplane transesophageal echocardiography is limited to the very proximal vessels. The numerous views provided by multiplane imaging may enhance visualization of coronary arteries and detection of their abnormalities. METHODS: Intraoperative multiplane transesophageal echocardiography was performed in 45 consecutive adults who had recently undergone angiography. Recordings were reviewed in blinded manner. RESULTS: We describe the coronary segments visualized with the different imaging planes and define new views. The left main coronary artery with its bifurcation was visualized in all 45 patients. Sensitivity and specificity for detection of coronary narrowings were 100% when results were compared with angiographic data. Visualization of proximal, mid and distal segments of the left anterior descending coronary artery was possible in 69%, 31% and 16% of patients, respectively. Among patients in whom the proximal segment was visualized, sensitivity and specificity for detection of significant narrowings were 80% and 100%. Proximal, mid and distal portions of the left circumflex coronary artery were visualized in 80%, 51% and 20% of patients. Among patients in whom the proximal portion was well seen, sensitivity and specificity were 89% and 100%. The proximal, mid and distal portions of the right coronary artery were visualized in 84%, 16% and 11% of patients. Among patients in whom the proximal segment was visualized, sensitivity and specificity were 82% and 100%. Color Doppler examination was less useful because it detected only 52% of all patients with proximal stenosis. CONCLUSIONS: Multiplane transesophageal echocardiography allows enhanced visualization of extended lengths of coronary arteries and the reliable identification of coronary artery abnormalities.

Left ventricular diastolic collapse in regional left heart cardiac tamponade. An experimental echocardiographic and hemodynamic study.

OBJECTIVES: This study was designed to describe the hemodynamic abnormalities associated with the appearance of left ventricular diastolic collapse in the setting of regional left heart cardiac tamponade. BACKGROUND: Cardiac tamponade after heart surgery is frequently associated with localized pericardial effusion. Although right ventricular diastolic collapse and right atrial collapse are reliable echocardiographic findings in patients with circumferential pericardial effusion and tamponade, they are often not present in postoperative patients with localized pericardial effusion and regional left heart tamponade. Left ventricular diastolic collapse has been described in such patients, but the degree of hemodynamic alteration that exists with this finding is not known. METHODS: Acute regional left heart tamponade was produced 14 times in seven spontaneously breathing anesthetized dogs by infusing fluid into an isolated compartment created in the pericardial space adjacent to the left ventricular free wall. Continuous echocardiographic imaging and hemodynamic monitoring of left ventricular, systemic arterial, right atrial, pulmonary capillary wedge and pericardial pressures were performed. Measurements at baseline were compared with those made at the onset of left ventricular diastolic collapse and at decompensated tamponade. RESULTS: Left ventricular diastolic collapse was noted in all 14 episodes of regional tamponade. It occurred when pressure in the left pericardial compartment exceeded left ventricular diastolic pressure by 3.0 +/- 1.9 mm Hg. At the onset of left ventricular diastolic collapse, cardiac output and mean arterial pressure were significantly reduced from the control value (p < 0.05). Systolic hypotension was noted only twice at this stage, respiratory variation in systolic pressure > 10 mm Hg only once. The appearance of this sign was also associated with elevated left heart filling pressures. CONCLUSIONS: Left ventricular diastolic collapse is a reliable sign of regional left ventricular tamponade and is associated with a reduction in cardiac output. This echocardiographic finding usually occurs before the development of arterial hypotension and pulsus paradoxus. Thus, left ventricular diastolic collapse is potentially more reliable than hypotension or pulsus paradoxus in the diagnosis of regional left ventricular tamponade.

Intravascular ultrasound imaging in acute aortic dissection.

OBJECTIVES: This study was performed to determine the potential of intravascular ultrasound in the detection and delineation of aortic dissection. BACKGROUND: Intravascular ultrasound is a new technique capable of displaying real-time cross-sectional images of arterial vasculature. Its clinical use has been explored mostly in coronary and peripheral arterial circulation. METHODS: Intravascular ultrasound imaging of the aorta was performed using a 20-MHz ultrasound catheter in 28 patients with suspected aortic dissection. All patients underwent contrast angiography; 7 had computed tomography; and 22 had transesophageal echocardiography. RESULTS: Imaging of the aorta from the root level to its bifurcation was performed in all patients in an average of 10 min. No complications occurred. Dissection was present in 23 patients and absent in 5. In the patients without dissection, intravascular ultrasound revealed normal aortic anatomy. In all 23 patients with dissection, intravascular ultrasound demonstrated the intimal flap and true and false lumena. The longitudinal and circumferential extent of aortic dissection, contents of the false lumen, involvement of branch vessels and the presence of intramural hematoma in the aortic wall could also be identified. In cases where aortography could not define the distal extent of the dissection, intravascular ultrasound did. CONCLUSIONS: Our experience in this series of patients with aortic dissection indicates that intravascular ultrasound could be valuable in the identification and categorization of aortic dissection and in the description of associated pathologic changes that may be clinically important. It can be performed rapidly and safely and could serve as an alternative or adjunct diagnostic procedure in patients with aortic dissection.

Physiologic significance of chronic coronary aneurysms in patients with Kawasaki disease.

OBJECTIVES: The aim of this study was to determine whether persistent coronary aneurysms in patients with Kawasaki disease are associated with altered myocardial perfusion and function. BACKGROUND: Some patients with Kawasaki disease have died suddenly because of severe coronary artery stenosis; others have chronic coronary aneurysms. METHODS: Eleven patients with chronic coronary aneurysms were enrolled in the study. The size of the aneurysms and the degree of associated stenosis were determined by angiography in nine patients and by echocardiography in two. All patients underwent simultaneous function and myocardial perfusion assessment during symptom-limited exercise by echocardiography and technetium-99m sestamibi imaging, respectively. RESULTS: Of 33 vascular territories, 18 contained coronary aneurysms measuring 3.5 to 10 mm. Three aneurysms were associated with significant stenosis as detected by angiography. Of the 18 vascular territories, 13 were normal, and 5 manifested stress-induced perfusion defects; of the latter 5 areas, 4 had associated wall motion abnormalities. The three territories supplied by stenotic coronary arteries had both abnormal regional function and perfusion demonstrated during exercise. CONCLUSIONS: Patients with chronic coronary aneurysms may have associated stenosis, as detected by angiography, with a subjacent myocardium that is subject to abnormal perfusion and function. However, the majority of coronary aneurysms are associated with normal regional coronary flow reserve, as assessed by myocardial perfusion imaging, and even giant coronary aneurysms may be associated with normal coronary flow reserve and preserved regional myocardial function during stress.

Intracardiac echocardiography in humans using a small-sized (6F), low frequency (12.5 MHz) ultrasound catheter. Methods, imaging planes and clinical experience.

OBJECTIVES: This study was designed to determine the clinical utility and feasibility of using 12.5-MHz ultrasound catheters for intracardiac echocardiography. BACKGROUND: Intracardiac echocardiography is a potentially useful technique of cardiac imaging and monitoring in certain settings. The feasibility of intracardiac echocardiography using 20-MHz ultrasound catheters in patients has been demonstrated. High resolution images of normal cardiac structures as well as cardiac abnormalities have been obtained. However, imaging has been limited by the shallow depth of field inherent in high frequency ultrasound imaging. METHODS: Intracardiac echocardiography with 12.5-MHz catheters was performed in eight mongrel dogs and 92 patients. Catheters were introduced percutaneously in 80 patients studied in the catheterization laboratory and directly into the heart in 12 patients in the operating room. Right heart imaging was performed in 68 patients and arterial and left heart imaging in 35 patients. RESULTS: When these catheters were introduced into the venous system, the right atrium, tricuspid valve, right ventricle, pulmonary valve and pulmonary artery were visualized. Pericardial effusion, intracardiac masses and atrial septal defects were correctly identified. The left ventricle, left atrium, mitral valve, aortic valve, aorta and coronary arteries could be imaged from the arterial circulation. Diseases identified included valvular aortic stenosis, subvalvular aortic stenosis and Kawasaki disease. Average imaging time was 10 min. No complications occurred as a result of intracardiac echocardiography. CONCLUSIONS: Intracardiac echocardiography with 12.5-MHz ultrasound catheters is safe and feasible; it also provides anatomic and physiologic information. This feasibility study provides a foundation for wider clinical use of intracardic echocardiography.

Use of an automated device for alternative site blood glucose monitoring.

OBJECTIVE: To evaluate the accuracy, comfort, and ease of use of a new automated device for blood glucose monitoring using the arm as an alternative sampling site. RESEARCH DESIGN AND METHODS: These studies use an automated hand-held device that applies a small vacuum, lances the skin, transfers blood onto an electrochemical test strip, and measures glucose. Patients who had type 1 or type 2 diabetes and had received no prior training using this device were recruited from five diabetes clinics. Testing was performed by the patients using this device and by trained healthcare professionals. Blood glucose was measured by 354 patients: from the arm using the device, from the finger using a laboratory reference instrument, and from the finger using the device via the secondary test port. Each patient completed a questionnaire rating the level of pain and ease of use of the device. RESULTS: Blood glucose results in samples obtained from the arm with the automated device agreed well with finger-stick plasma glucose results using a reference instrument (regression slope 0.98, intercept 0.01 mmol/l [0.1 mg/dl], r = 0.96). Error grid analysis showed that 100% of the measurements fell within zones A and B. In the survey, 60% of the patients reported that arm testing with the automated device was "painless;" another 31% of the patients stated that it was "much less painful," and 6% of patients considered using the device "less painful" than finger-stick testing. In a survey containing 15 questions for rating the ease of use with a scale of 1 to 6, the overall mean rating was 5.5. CONCLUSIONS: The automated device is easy to use and provides accurate glucose results; 97% of the patients found it less painful than finger-stick testing.

Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin.

OBJECTIVE: To determine the safety and efficacy of the long-acting analog insulin glargine compared with NPH insulin in patients with type 2 diabetes who were previously treated with insulin alone. RESEARCH DESIGN AND METHODS: A total of 518 subjects with type 2 diabetes who were receiving NPH insulin with or without regular insulin for postprandial control were randomized to receive insulin glargine (HOE 901) once daily (n = 259) or NPH insulin once or twice daily in = 259) for 28 weeks in an open-label, multicenter trial. Doses were adjusted to obtain target fasting glucose <6.7 mmol/l. At study end point, the median total daily insulin dose in both treatment groups was 0.75 IU/kg. RESULTS: The treatment groups showed similar improvements in HbA1c from baseline to end point on intent-to-treat analysis. The mean change (means +/- SD) in HbA1c from baseline to end point was similar in the insulin glargine group (-0.41 +/- 0.1%) and the NPH group (-0.59 +/- 0.1%) after patients began with an average baseline HbA1c of approximately 8.5%. The treatments were associated with similar reductions in fasting glucose levels. Overall, mild symptomatic hypoglycemia was similar in insulin glargine subjects (61.4%) and NPH insulin subjects (66.%) However, nocturnal hypoglycemia in the insulin glargine group was reduced by 25% during the treatment period after the dose-titration phase(26.5 vs. 35.5%, P = 0.0136). Subjects in the insulin glargine group experienced less weight gain than those in the NPH group (0.4 vs. 1.4 kg, P < 0.0007). CONCLUSIONS: In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once- or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine deonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin.

Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes.

OBJECTIVE: This study compared the effects of nateglinide, glyburide, and placebo on postmeal glucose excursions and insulin secretion in previously diet-treated patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks. Glucose, insulin, and C-peptide profiles during liquid meal challenges were measured at weeks 0 and 8. At weeks -1 and 7, 19-point daytime glucose and insulin profiles, comprising three solid meals, were measured. RESULTS: During the liquid-meal challenge, nateglinide reduced the incremental glucose area under the curve (AUC) more effectively than glyburide ( = -4.94 vs. -2.71 mmol. h/l, P < 0.05), whereas glyburide reduced fasting plasma glucose more effectively than nateglinide ( = -2.9 vs. -1.0 mmol/l, respectively, P < 0.001). In contrast, C-peptide induced by glyburide was greater than that induced by nateglinide ( = +1.83 vs. +0.95 nmol. h/l, P < 0.01), and only glyburide increased fasting insulin levels. During the solid meal challenges, nateglinide and glyburide elicited similar overall glucose control ( 12-h incremental AUC = -13.2 vs. -15.3 mmol. h/l), but the insulin AUC induced by nateglinide was significantly less than that induced by glyburide ( 12-h AUC = +866 vs. +1,702 pmol. h/l, P = 0.01). CONCLUSIONS: This study demonstrated that nateglinide selectively enhanced early insulin release and provided better mealtime glucose control with less total insulin exposure than glyburide.

Promotion and acceleration of diabetic ulcer healing by arginine-glycine-aspartic acid (RGD) peptide matrix. RGD Study Group.

OBJECTIVE: To determine the effectiveness and safety of arginine-glycine-aspartic acid (RGD) peptide matrix in the treatment of diabetic foot ulcers. RESEARCH DESIGN AND METHODS: This randomized placebo-controlled investigator- and patient-blinded prospective multicenter investigation was conducted at three institutional and three private U.S. clinics providing ambulatory care. Sixty-five diabetic patients with chronic full-thickness neurotrophic foot ulcers were enrolled. Six discontinued the study because of adverse events. RGD peptide matrix (Argidene Gel; formerly Telio-Derm Gel) was applied topically twice weekly for up to 10 weeks in patients who otherwise received standard care. Control group patients received topical saline as a placebo plus standard care. The primary method of assessment was the incidence and rate of ulcer closure. All patients enrolled were included in the data analysis. RESULTS: The percentage of patients whose ulcers healed completely in the RGD peptide matrix group (35%; 14 of 40 patients) was over fourfold greater (P = 0.02) than that in the placebo group (8%; 2 of 25 patients). By the study end point (either day of healing or week 10), 30 of 40 (75%) RGD peptide matrix patients had achieved > 50% ulcer closure compared with 12 of 25 (48%) placebo patients (P = 0.03). RGD peptide matrix also significantly (P = 0.03) increased the rate of ulcer closure over the 10 weeks of the study. CONCLUSIONS: RGD peptide matrix treatment promoted and accelerated the healing of chronic diabetic foot ulcers to a significant degree.

A quantitative difference between immunologically and biologically active prolactin in hypothyroid patients.

Under certain conditions, the pituitary may secrete PRL species displaying diverse immunological and biological activities. To study this phenomenon further, we compared PRL determined by RIA and radioreceptor assay (RRA) in 25 hypothyroid patients (TSH, greater than 10 microU/ml) and in 49 endocrinologically normal patients. In the normal women, the ratio of the PRL mean determined by RRA (67.3 ng/ml) to that determined by RIA (13.5 ng/ml) was 4.99 +/- 0.435. By contrast, in hypothyroid patients, PRL determined by RRA was significantly lower than the value determined by RIA for each patient, and the ratio of means (RRA to RIA) was 0.782 +/- 0.067. The mean PRL determined by RRA (52.2 ng/ml) was not significantly different from the mean of control patients (P greater than 0.5). PRL determined by RIA was elevated in all hypothyroid patients (range, 24-237 ng/ml), and the mean (by RIA) (64.1 ng/ml) was significantly elevated above the mean PRL (by RIA) of controls (P less than 0.000001). Thus, in the chronically hypothyroid patients, PRL is characterized as possessing normal receptor-binding activity and augmented immunological activity.

Retrospective study of 2,200 involuntary psychiatric admissions and readmissions.

OBJECTIVE: The authors describe demographic data, the distribution of diagnoses, and comorbid psychoactive substance use in a large sample of patients involuntarily admitted to a psychiatric hospital from multiple crisis centers and explore the relative roles these variables may play in service utilization and admission rates. METHOD: Data on demographic characteristics and comorbid psychoactive substance use in 2,200 consecutive involuntary hospital admissions of 1,755 psychiatric patients were gathered. Pertinent demographic and comorbidity data at first admission for the 1,755 patients, 314 of whom were admitted more than once, were analyzed; then the data for the 1,441 single-admission patients and the data at first admission for the 314 patients who had multiple admissions were compared. Finally, the diagnostic distribution and comorbid psychoactive substance use in all 2,200 admissions were investigated, with attention to a subgroup of 88 high-risk patients (those with three or more admissions) who represented a total of 307 admissions. RESULTS: Specific demographic characteristics were represented in the patient group at a high level of statistical significance. The diagnosis of schizophrenia was significantly overrepresented. Schizophrenia and psychosis not elsewhere classified clustered in the subgroup with a high risk of readmission. CONCLUSIONS: The results suggest a specific profile for the patient with heightened risk of hospital admission: a young, unmarried, African American male who has schizophrenia without comorbid substance abuse. An effect size data analysis identified marital status and a diagnosis of schizophrenia as the variables associated with the greatest likelihood of admission. Unexpectedly, the impact of comorbid psychoactive substance use was relatively modest and showed a uniform distribution among diagnostic groups.

Effects of short-term insulin therapy upon therapeutic response to glipizide.

The effect of glipizide alone and glipizide preceded by a short course of insulin therapy (10 weeks) was studied in 69 patients with non-insulin-dependent diabetes mellitus (NIDDM) in a 10-month study. The patients were obese, had poor glycemic control, and, in all patients, first-generation sulfonylurea therapy had failed. The majority were Mexican-Americans, an ethnic population with a high incidence of NIDDM and insulin resistance. Plasma glucose levels were monitored using the eight-point [Saarstedt] series. In the group receiving glipizide alone, mean fasting plasma glucose levels decreased from 255.9 mg/dl at baseline to 228.7 mg/dl at the end of the study; two-hour postprandial glucose levels decreased from 280.1 to 260.5 mg/dl; glycosylated hemoglobin decreased from 9.1 to 7.4 percent; and post-Sustacal C-peptide levels increased from 0.7 to 1.0 pmol/ml. In the group receiving insulin/glipizide, mean fasting plasma glucose levels decreased from 241.1 mg/dl at baseline to 217.0 mg/dl; two-hour postprandial glucose levels increased from 267.2 to 279.0 mg/dl; glycosylated hemoglobin decreased from 9.1 to 7.5 percent; and post-Sustacal C-peptide levels increased from 0.6 to 1.0 pmol/ml. At the end of 10 weeks, insulin administration was associated with a more rapid decrease in the levels of fasting plasma glucose, two-hour postprandial glucose, and glycosylated hemoglobin, but there was no significant difference between the two therapies by the end of the study. Both regimens had a positive influence on reducing the total cholesterol/high-density lipoprotein ratio. More patients in the group receiving insulin/glipizide withdrew from the study, which may have been due to difficulties associated with insulin administration. In conclusion, there does not appear to be a prolonged effect of insulin treatment on the post-receptor defect. Some patients in whom first-generation oral agents fail may not have to be given permanent insulin therapy, especially those with fasting plasma glucose levels of less than 200 mg/dl. There was no overall difference between these treatments with respect to glycemic control or lipoprotein profiles. In the interests of simplifying both therapy and monitoring, enhancing patient compliance, and achieving cost reductions, therapy with glipizide alone ultimately may be sufficient for cases in which immediate control is unnecessary (for example, patients with asymptomatic hyperglycemia, and in the absence of hyperlipidemia and vascular disease).