Postprandial glucose and HbA1c are associated with severity of obstructive sleep apnoea in non-diabetic obese subjects.

INTRODUCTION: Obstructive sleep apnoea (OSA) is an underdiagnosed condition frequently associated with glycaemic control impairment in patients with type 2 diabetes. AIM: To assess the relationship between glycometabolic parameters and OSA in obese non-diabetic subjects. METHODS: Ninety consecutive subjects (mean age 44.9 ± 12 years, mean BMI 42.1 ± 9 kg/m2) underwent polysomnography and a 2-h oral glucose tolerance test (OGTT). RESULTS: OSA was identified in 75% of subjects, with a higher prevalence of males compared to the group of subjects without OSA (62% vs 32%, p = 0.02). Patients with OSA had comparable BMI (42.8 kg/m2 vs 39.4 kg/m2), a higher average HbA1c (5.8% vs 5.4%, p < 0.001), plasma glucose at 120 min during OGTT (2 h-PG; 123 mg/dl vs 97 mg/dl, p = 0.009) and diastolic blood pressure (81.1 mmHg vs 76.2 mmHg, p = 0.046) than obese subjects without OSA. HbA1c and 2 h-PG were found to be correlated with the apnoea-hypopnoea index (AHI; r = 0.35 and r = 0.42, respectively) and with percent of sleep time with oxyhaemoglobin saturation < 90% (ST90; r = 0.44 and r = 0.39, respectively). Further, in a linear regression model, ST90 and AHI were found to be the main determinants of 2 h-PG (ß = 0.81, p < 0.01 and ß = 0.75, p = 0.02, respectively) after controlling for age, sex, waist circumference, physical activity, and C-reactive protein. Similarly, ST90 and AHI persisted as independent determinants of HbA1c (ß = 0.01, p = 0.01 and ß = 0.01, p = 0.01, respectively). CONCLUSION: Beyond the traditional clinical parameters, the presence of a normal-high value of 2 h-PG and HbA1c should raise suspicion of the presence of OSA in obese subjects.

Bupropion Hydrochloride.

Bupropion hydrochloride is a norepinephrine-dopamine disinhibitor (NDDI) approved for the treatment of depression and smoking cessation. Bupropion is a trimethylated monocyclic phenylaminoketone second-generation antidepressant, which differs structurally from most antidepressants, and resides in a novel mechanistic class that has no direct action on the serotonin system. Comprehensive chemical, physical, and spectroscopic profiles are presented. This analytical profile provides an extensive spectroscopic investigation utilizing mass spectrometry, one- and two-dimensional NMR, solid-state NMR, IR, NIR, Raman, UV, and X-ray diffraction. The profile also includes significant wet chemistry studies for pH, solubility, solution, and plasma stability. Both HPLC and UPLC methodology are presented for bupropion and its related impurities or major metabolites. The profile concludes with an overview of biological properties that includes toxicity, drug metabolism, and pharmacokinetics.

Pacemaker lead perforation of the right ventricle associated with Moraxella phenylpyruvica infection in a dog.

CASE DESCRIPTION: A 13-year-old neutered male Border Collie was presented with acute onset syncope, weakness and anorexia 10 months after transvenous pacemaker implantation. The patient was laterally recumbent, bradycardic (36 beats/min) and febrile (40.7°C) on presentation. An electrocardiogram (ECG) revealed recurrence of third-degree atrioventricular block with a ventricular escape rhythm. Fluoroscopy identified migration of the pacemaker tip through the apex of the right ventricle. Echocardiography failed to reveal any evidence of pericardial effusion or cardiac tamponade. Full postmortem was performed after euthanasia. The pacemaker lead had perforated the apex of the right ventricle and lodged in the right pleural space. Culture of blood (taken antemortem), pericardial sac, right ventricular wall (surrounding pacemaker lead), pacemaker lead tip and pericardial fluid revealed a pure growth of Moraxella phenylpyruvica. CONCLUSION: Bacteraemia associated with M. phenylpyruvica has never been reported in the dog, but sporadic cases are reported in humans. Infection could have resulted from either pre-existing myocarditis or opportunistic infection and bacteraemia post pacemaker implantation. Evaluation of the pacemaker function at regular intervals would allow early detection of poor pacemaker-to-myocardium contact, which would prompt further investigation of pacemaker lead abnormalities such as perforation.

Transition from pediatric to adult care. eight years after the transition from pediatric to adult diabetes care: metabolic control, complications and associated diseases.

BACKGROUND: Transition from pediatric to adult care is a critical process in the life of patients with diabetes. AIM: Primary aim of the study was to compare the metabolic control between pediatric care and adult care at least 5 years in a group of patients with type 1 diabetes mellitus (T1DM). Secondary aim was to evaluate the presence of complications, associated diseases and psychological-psychiatric disorders. SUBJECTS AND METHODS: We obtained data from 73 % (69/94) patients (current mean age 34 years) transferred to local adult centers between 1985 and 2005 at a mean age of 23.8 years. Data were collected for HbA1c, diabetic complications and associated diseases. RESULTS: Mean HbA1c did not change during the pediatric, transition and adult period [8.4 ± 1.8 % (68 ± 18 mmol/mol), 8.3 ± 1.4 % (67 ± 15 mmol/mol) and 8.4 ± 1.3 % (68 ± 14 mmol/mol), respectively]. 13 patients dropped out, after 2-12 years since transition, and their HbA1c mean value at transition was 10.4 %. After a mean of 25.9 years of disease, 35/69 patients (50.7 %) showed retinopathy, and 12/69 patients (17.3 %) nephropathy. Thyroid diseases were the most frequent associated diseases (18.3 %), followed by depression (11.2 %) and benign neoplasms (9.8 %). Drug or alcohol addictions were present in four cases (5.6 %). CONCLUSIONS: After a mean follow-up of 8 years metabolic control after transition did not change significantly in patients constantly attending to adult care centre. Patients with diabetes onset between 20 and 40 years ago were free from complications in 50 % of cases when considering retinopathy and in more than 80 % considering nephropathy. Thyroid problems were the most common associated diseases. Poor metabolic control at transition is associated with higher risk of drop-out and psychosocial morbidity.

A modern view of excipient effects on bioequivalence: case study of sorbitol.

PURPOSE: To examine the effect of common excipients such as sugars (sorbitol versus sucrose) on bioequivalence between pharmaceutical formulations, using ranitidine and metoprolol as model drugs. METHODS: Two single-dose, replicated, crossover studies were first conducted in healthy volunteers (N=20 each) to compare the effect of 5 Gm of sorbitol and sucrose on bioequivalence of 150 mg ranitidine or 50 mg metoprolol in aqueous solution, followed by a single-dose, nonreplicated, crossover study (N=24) to determine the threshold of sorbitol effect on bioequivalence of 150 mg ranitidine in solution. RESULTS: Ranitidine Cmax and AUC0-infinity were decreased by approximately 50% and 45%, respectively, in the presence of sorbitol versus sucrose. Similarly, sorbitol reduced metoprolol Cmax by 23% but had no significant effect on AUC0-infinity. An appreciable subject-by-formulation interaction was found for ranitidine Cmax and AUC0-infinity, as well as metoprolol Cmax. Sorbitol decreased the systemic exposure of ranitidine in a dose-dependent manner and affected bioequivalence at a level of 1.25 Gm or greater. CONCLUSIONS: As exemplified by sorbitol, some common excipients have unexpected effect on bioavailability/bioequivalence, depending on the pharmacokinetic characteristics of the drug, as well as the type and amount of the excipient present in the formulation. More research is warranted to examine other 'common' excipients that may have unintended influence on bioavailability/bioequivalence.

Enhanced pressor responsiveness to norepinephrine in type II diabetes. Effect of ACE inhibition.

OBJECTIVE: To evaluate the effect of angiotensin-converting enzyme (ACE) inhibition on the pressor responsiveness to norepinephrine in type II diabetes. RESEARCH DESIGN AND METHODS: Eight normotensive subjects, eight mild-to-moderate hypertensive type II diabetic patients, and eight nondiabetic patients with essential hypertension were studied before and after 4 weeks of being administered enalapril. The pressor response to norepinephrine was assessed by infusing the hormone in an antecubital vein at incremental doses of 30 ng.kg-1.min-1 for periods of 5 min until reaching an increase of 20 +/- 2 mmHg in mean arterial pressure (MAP) measured by an automatic device at 1-min intervals. An effective dosage of norepinephrine that increased MAP by 20 mmHg (EDNE 20) was thereafter calculated. Before and during the last minute of norepinephrine infusion at maximum dosage, a venous blood sample was drawn to determine plasma renin activity (PRA), aldosterone, and norepinephrine levels. RESULTS: In the three groups of patients, blood pressure and aldosterone were reduced while PRA was raised following ACE inhibition. Basal and maximum postinfusion levels of norepinephrine were not modified by enalapril. The EDNE 20 was basally lower in diabetic patients and remained unchanged after ACE inhibition, contrary to that observed in nondiabetic patients with essential hypertension. CONCLUSIONS: Both normotensive and hypertensive type II diabetic patients have an increased pressor responsiveness to norepinephrine that is not modified by therapeutic doses of enalapril, contrary to what is observed in nondiabetic patients with essential hypertension.

[Diabetic nephropathy and pregnancy]. / Nefropatia diabetica e gravidanza.

During pregnancy, the kidneys of diabetic women undergo an elevated functional load which occurs to a greater extent if nephropathy coexists. Functional abnormalities, such as reduction of glomerular filtration rate, increase of creatinine and proteinuria, which can be observed in about 1/3 of the cases, regress or stabilize progressing only in a limited number of patients. Arterial hypertension and poor metabolic control seem to be the factors most closely correlated to the loss of renal function. Diabetic nephropathy determines an increased risk of maternal and fetal complications to be seen more frequently in women with more compromised renal function at conception, and with poor metabolic control during pregnancy. From here stems the importance of good metabolic control right from conception. Moderate physical exercise, a caloric intake of 25-35 kcal/kg/day and slight reduction of protein diet content are also advisable. Monitoring includes periodical evaluation of glycated haemoglobin, creatinine, uric acid, creatinine clearance and albuminuria not only during pregnancy but also after months or years following delivery. Arterial pressure must be monitored avoiding aggressive antihypertensive treatment. The most suitable drugs are considered alfa-methyldopa, clonidine, hydralazine and prazosine.

Angiographic evaluation of the anatomic pattern of arterial obstructions in diabetic patients with critical limb ischaemia.

OBJECTIVE: The present study was undertaken to evaluate, by means of angiography, the anatomic pattern of arterial obstructions in the lower extremities of diabetic patients presenting with critical limb ischaemia. We particularly examined the differences in involvement of the foot arteries between patients with and without diabetes. PATIENTS AND METHODS: A group of 150 patients with limb-threatening ischaemia, manifested by rest pain and/or non-healing ischaemic ulcers or gangrene, underwent angiologic evaluation in prevision of vascular surgery. The patients, of whom 89 were suffering from diabetes, were examined by means of digital subtraction angiography using the Seldinger technique. In each patient, details of arterial tree were obtained from the aortoiliac to the foot arteries and the site and the extent of obstructions were determined blindly with the radiologist unaware of the patient's history of diabetes. RESULTS: Diabetic patients showed significantly more obstructions in the infrapopliteal arteries when compared to the patients without diabetes who had more pronounced involvement of aortoiliac and femoropopliteal arteries. Diabetic patients, moreover, showed a higher prevalence of obstruction in posterior tibial, peroneal and plantar arteries than the non-diabetics. At the time of presentation, the age of patients did not differ between the two groups but diabetic patients had more frequent ischaemic ulcers or gangrene and less rest pain than the non-diabetics. CONCLUSIONS: Our study confirms earlier reports carried out with non-angiographic methods indicating more frequent involvement of calf arteries in diabetic patients but disagrees with those which report that patients with diabetes have less occlusive disease in foot arteries.

Low-dose angiotensin converting enzyme inhibitors: effect on renal function in normo- and hypertensive type 1 diabetic patients.

OBJECTIVES: To investigate the effect of low doses of the angiotensin converting enzyme inhibitor enalapril on renal haemodynamics and albuminuria in normotensive and hypertensive type 1 (insulin-dependent) diabetic patients with incipient or overt nephropathy. METHODS: Twenty-two type 1 (insulin-dependent) diabetic patients with persistent microalbuminuria or macroalbuminuria and normal serum creatinine were studied. Of all patients, 16 males and 6 females, age 45 +/- 13 years, diabetes duration 19 +/- 11 years, insulin dose 38 +/- 11 U/day, 10 were normotensive and 12 were hypertensive. After 3 months of run-in period the patients were assigned to treatment with 5 mg or 10 mg enalapril based on the presence of normotension or hypertension respectively. Before and after 6 months of treatment, renal function was assessed by evaluation of glomerular filtration rate (99m Tc-DTPA), renal plasma flow (131-I iodohippurate), filtration fraction and renal vascular resistance. Mean arterial pressure, albumin excretion rate, urinary urea excretion and glycated haemoglobin were also determined. RESULTS: Administration of enalapril resulted in both groups of patients in a significant fall in mean arterial pressure, albumin excretion rate, glomerular filtration rate, filtration fraction, and renal vascular resistance. Decreasing albumin excretion did not correlate with a drop in systemic blood pressure or filtration fraction. No significant variations were observed in renal plasma flow, in urinary urea excretion or in glycated haemoglobin. CONCLUSIONS: Our results suggest that low doses of enalapril are effective in influencing renal haemodynamics and reducing urinary albumin excretion in both normotensive and hypertensive type 1 (insulin-dependent) diabetic patients with incipient or overt nephropathy. The lowering effect of the angiotensin converting enzyme inhibitor on albuminuria seems to be independent of the action on systemic blood pressure and renal haemodynamic changes.

ACE inhibition in diabetic patients: effect on pressor responsiveness to noradrenaline.

The pressor responsiveness to noradrenaline was assessed before and after four weeks of treatment with enalapril (20 mg/day) in eight mild-to-moderate essential hypertensives, in eight normotensive type II diabetics and in eight mild-to-moderate hypertensive type II diabetic patients. The ACE inhibitor interfered to the same extent with the renin-angiotensin system and did not alter noradrenaline kinetics in the three groups of patients, but significantly reduced the arterial responsiveness only in non-diabetic subjects. It is suggested that factors, such as an exaggerated sodium retention, might determine the lack of effect of enalapril in diabetic patients.

Intra-arterial urokinase infusion in diabetic patients with rapidly progressive ischemic foot lesions.

OBJECTIVE: The effectiveness of local intra-arterial thrombolysis by urokinase was evaluated in eight non-insulin-dependent diabetic patients with angiographic evidence of infrapopliteal occlusive disease and rapidly progressive foot lesions. RESEARCH DESIGN AND METHODS: With an electric peristaltic pump, urokinase was infused for 96 h by a 5-6 F catheter introduced into the femoral artery and placed immediately above the occluded infrapopliteal arteries. After baseline, angiography was repeated at 24- to 48-h intervals and at conclusion of the treatment. RESULTS: Six patients showed immediate improvement of clinical symptoms. Angiography revealed the reestablishment of blood flow in collateral vessels of the leg and foot in the dorsal pedal artery in three patients and in the plantar arch in two. Recanalization of the major arteries of the trifurcation was not achieved. After 12 mo of follow-up, all limbs were salvaged, although four patients required vascular reconstruction to further improve foot perfusion and complete healing. CONCLUSIONS: Intra-arterial urokinase, which opens collateral and smaller vessels of the leg and foot in patients with diabetes, may be effective in improving blood flow in lower extremities and in making the patient a better candidate for vascular surgery.

The effect of ace inhibition on peripheral hemodynamics in normotensive and hypertensive patients with type II diabetes.

The effect of treatment with enalapril (10 days at 10 mg/d followed by 4 weeks at 20 mg/d) on forearm hemodynamics was assessed in eight normotensive patients and eight patients with hypertension affected by Type II diabetes as well as in eight patients with essential hypertension and normal glucose tolerance. The ACE inhibitor decreased regional vascular resistances and increased the maximum arteriolar-vasodilating capacity and venous distensibility in the three groups of patients. Thus, this study shows that ACE inhibition by enalapril improves regional hemodynamics in patients with Type II diabetes.

A screening test for microalbuminuria in type 1 (insulin-dependent) diabetes.

In this study we evaluated the acceptability of using the first morning urine albumin concentration (FMAC) and the first morning urine albumin/creatinine (FMA/C) ratio as an indirect estimation of timed albumin excretion in order to screen for microalbuminuria in a large diabetic population. Urinary albumin excretion rate (AER) was determined in samples from 4-h urine collection in 99 type 1 diabetic patients aged 30 +/- 10 years with a mean duration of diabetes of 15 +/- 8 years. The results of timed albumin excretion were successively compared with single-void first morning samples. On the basis of AER, 46 patients were normoalbuminuric (AER less than 20 micrograms/min), 28 microalbuminuric (AER 20-200 micrograms/min), and 25 proteinuric (AER greater than 200 micrograms/min). The relationship of 4-h AER to FMAC and FMA/C ratio was highly significant (r = 0.96 and r = 0.98 respectively). High sensitivity and specificity were found when cut-offs of 20 micrograms/ml and 2.5 mg/mmol were selected for albumin concentration and albumin/creatinine ratio respectively to discriminate between normal and elevated albuminuria. It is concluded that the measurements of albumin concentration and albumin/creatinine ratio in first morning urine samples are highly representative of 4-h timed albumin excretion. Because of their sensitivity, specificity and simplicity to perform, the tests proposed might be used in routine diabetic care and as a screening test for microalbuminuria in type 1 (insulin-dependent) diabetic patients. The not negligible day-to-day variability in albumin excretion confirms the need of several measurements to establish the presence of abnormal levels of albuminuria above all in patients with borderline values and/or clinically unstable metabolic control.

Oesophageal transit time and cardiovascular autonomic neuropathy in type 1 (insulin-dependent) diabetes mellitus.

Oesophageal computerized dynamic scintigraphy with 99 mTc was used to evaluate oesophageal motility in type 1 (insulin-dependent) diabetic patients without upper gastrointestinal symptoms. Twenty-nine patients, 10 women and 19 men, mean age 38 +/- 12 yr (range 17-55), mean duration of diabetes 15 +/- 8 yr (range 3-30) and 15 controls were studied. Background or proliferative retinopathy was found in 72.4% of patients, incipient or clinical nephropathy in 48.3% and peripheral neuropathy in 62% of them. In all, oesophagitis and/or other disorders of the upper gastrointestinal tract were excluded by barium studies and endoscopy. Oesophagus scintigraphy with 99 mTc sulphur colloid was performed in each subject after fasting for at least 3 hr in the supine position and repeated after few minutes to assess its reproductivity. The rate of passage of the fluid bolus through oesophagus was analyzed by computer and oesophageal transit time (OTT) for the whole oesophagus was measured by time-activity curves. All diabetic patients were screened for autonomic cardiovascular function by standard tests and, on the base of results, assigned to cardiovascular autonomic neuropathy positive (CVAN-positive) or to cardiovascular autonomic neuropathy negative (CVAN-negative) group. Abnormal oesophageal motility (OTT less than 14 sec as mean +/- 2 SD of controls) was found in 68.7% of CVAN-positive and in 15.4% of CVAN-negative patients (p less than 0.05). CVAN-positive patients resulted older and had significantly longer duration of diabetes than other patients. Furthermore, they showed higher frequency of severe retinopathy, nephropathy, peripheral neuropathy and prolonged OTT compared with CVAN-negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperglycemic effect of sucrose ingestion in IDDM patients controlled by artificial pancreas.

The hyperglycemic effect of 28 g sucrose, taken during a mixed meal, was studied in six insulin-dependent diabetes mellitus (IDDM) patients controlled by artificial pancreas. On 2 consecutive days the patients were given, in random order, two Italian meals containing macaroni, bread, meat, vegetables, fruit, olive oil, and an eggnog made with sucrose (meal A) or saccharin (meal B). The two meals were isocaloric and contained equal amounts of carbohydrates. The feedback control on blood glucose continued for 180 min after the meals. Plasma glucose levels and insulin infusion rates delivered by the artificial pancreas after the two test meals did not show any significant differences regarding basal and peak values, peak times, and areas under the curves. A modest amount of sucrose, taken during a mixed meal, does not produce a hyperglycemic effect higher than an equal amount of complex carbohydrates in IDDM patients controlled by artificial pancreas. The same may be expected in well-controlled IDDM patients in conventional therapy because a correlation exists between insulin requirement for conventional therapy and insulin delivered during glucose-controlled insulin infusion.

Possible effectiveness of plasmapheresis and immunosuppressive therapy in reversing subcutaneous insulin resistance: a case report.

Severe resistance to subcutaneous insulin with normal sensitivity to intravenous insulin developed in a 39 year old woman affected by type 1 diabetes mellitus. The patient had been treated for ten months with continuous intravenous or intraperitoneal insulin before undergoing pancreatic transplantation. After surgery repeated plasmapheresis were performed and immunosuppressive therapy was undertaken. When studied again, one month after surgery, the patient showed normal sensitivity to subcutaneous insulin. Our data suggest that plasmapheresis and/or immunosuppressive treatment could have played a role in reversing insulin resistance.