A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin.

AIMS: To test the hypothesis that glycaemic control achieved when switching sitagliptin to exenatide twice daily plus metformin is non-inferior to adding exenatide twice daily to sitagliptin and metformin. METHODS: Patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin were randomly assigned to 20 weeks of treatment with twice-daily exenatide plus placebo and metformin (SWITCH, n = 127) or twice-daily exenatide plus sitagliptin and metformin (ADD, n = 128). RESULTS: Non-inferiority (0.4% margin) of SWITCH to ADD treatment, measured by change in HbA(1c) from baseline to week 20, was not shown {between-treatment difference in least-squares mean [95% CI 3 mmol/mol (0.30%)] [0.8-5.8 (0.07-0.53)]}. A greater reduction (P = 0.012) in HbA(1c) [least-squares mean (se)] was experienced by patients in the ADD group {-7 mmol/mol [-0.68%] [0.9 (0.08)]}, compared with those in the SWITCH group {-4 mmol/mol [-0.38%] [1.0 (0.09)]} and a greater proportion (P = 0.027) of patients in the ADD group (41.7%) reached < 7.0% (< 53 mmol/mol) HbA(1c) target, compared with those in the SWITCH group (26.6%) by week 20. Patients in the ADD group experienced greater fasting serum glucose (P = 0.038) and daily mean postprandial self-monitored blood glucose (P = 0.048) reductions, compared with patients in the SWITCH group, by week 20. Patients in both groups experienced a lower incidence of nausea and vomiting compared with previous exenatide studies. CONCLUSIONS: Non-inferiority of SWITCH to ADD treatment was not supported by the results of this study. In patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin, adding exenatide provided better glycaemic control than switching to exenatide. These results are consistent with the clinical approach that adding is better than switching to another oral anti-hyperglycaemic medication.

An algorithm for the treatment of type 2 diabetes in Latin America.

Diabetes is a principal and growing health concern in Latin America, accounting for significant mortality and morbidities. Large, randomized, prospective trials of various interventional therapies in patients with both type 1 and type 2 diabetes have demonstrated that reductions in hyperglycaemia and management of diabetes-related risk factors can significantly reduce the micro- and macrovascular complications of diabetes. Therefore, patients with type 2 diabetes will benefit from more aggressive treatment regimens to help decrease the occurrence and rate of progression of diabetic complications. Given the many complexities of diabetes management, it is often difficult for general practice physicians to stay abreast of emerging treatment strategies and therapies. Owing to the high prevalence of type 2 diabetes in Latin America, the majority of patients with diabetes are treated by generalists rather than specialists. This article was intended to assist physicians and other healthcare professionals in developing and using effective treatment strategies to stem the growing epidemic of diabetes and its complications in Latin America.

Yohimbine in neurally mediated syncope. Pathophysiological implications.

In this study, we evaluated if increased sympathetic stimulation is an essential requirement for the development of neurally mediated syncope (NMS) by manipulating overall sympathetic outflow in subjects susceptible to tilt-induced syncope. Eight previously characterized patients with recurrent NMS (five females and three males; 34+/-2 yr) were recruited from the Vanderbilt Syncope Unit and eight age-matched controls underwent initial administration of clonidine (CLO) or yohimbine (YHO). This was done, prospectively, to determine doses of these agents that would increase or decrease plasma norepinephrine levels by >/= 30%. On a different day, in all subjects we determined intraarterial blood pressure, EKG and muscle sympathetic nerve activity (MSNA) both supine and during upright tilt. After this, subjects randomly received either CLO or YHO, and 3 h later another tilt was performed. After 1 wk, a similar procedure with the other drug was performed. During the two basal tilts, all the control subjects completed the study, whereas all the NMS patients developed syncope. Reduction in sympathetic tone by CLO resulted in a decreased tolerance to tilt in three out of eight controls and in all the NMS patients. In contrast, YHO not only increased basal plasma NorEpi levels and MSNA, but also prevented syncope in seven out of eight patients. In a selected population of patients, increased sympathetic activity is not a prerequisite for the development of syncope. Yohimbine-induced enhancement of sympathetic tone in patients with NMS improves orthostatic tolerance and raises the possibility that this drug may be a useful agent in the treatment of NMS.

Modulatory effects of endothelin on baroreflex activation in the nucleus of the solitary tract.

In this study, we determine the effects of endogenous endothelin on baroreflex activation. After control baroreflex slopes were obtained, the animals received bilateral intra-nucleus tractus solitarii microinjections of saline, or equimolar doses (4 pmol/60 nl) of the endothelin ETA receptor antagonist cyclo (D-Trp-D-Asp-Pro-Val-Leu (BQ-123), Homopiperinidinyl-CO-Leu-D-Trp(CHO)-D-Trp-OH (BQ-610), or the endothelin ETB receptor antagonist N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-MeLeu-D-Trp( COOCH3)-D-Nle (BQ-788). Intra-nucleus tractus solitarii administration of BQ-123 resulted in a brief initial pressor effect followed by hypotension which resolved by 15 min. The baroreflex slope was significantly enhanced when tested 15 min after BQ-123 treatment (from 2.4 +/- 0.5 ms/mmHg to 3.5 +/- 0.4 ms/mmHg). Similar effects were observed with the other endothelin ETA receptor antagonist, except that the hypertensive and hypotensive responses were more pronounced while the baroreflex slope was similarly increased. In contrast, the endothelin ETB receptor antagonist did not evoke appreciable changes in hemodynamics or in baroreflex slopes. Our results support the concept that endothelin prominently affects reflex cardiovascular function through the endothelin ETA receptor subtype.

Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt.

The pathophysiology of neurally mediated syncope is poorly understood. It has been widely assumed that excessive sympathetic activation in a setting of left ventricular hypovolemia stimulates ventricular afferents that trigger hypotension and bradycardia. We tested this hypothesis by determining if excessive sympathetic activation precedes development of neurally mediated syncope, and if this correlates with alterations in baroreflex function. We studied the changes in intraarterial blood pressure (BP), heart rate (HR), central venous pressure (CVP), muscle sympathetic nerve activity (MSNA), and plasma catecholamines evoked by upright tilt in recurrent neurally mediated syncope patients (SYN, 5+/-1 episodes/mo, n = 14), age- and sex-matched controls (CON, n = 23), and in healthy subjects who consistently experienced syncope during tilt (FS+, n = 20). Baroreflex responses were evaluated from changes in HR, BP, and MSNA that were obtained after infusions of phenylephrine and sodium nitroprusside. Compared to CON, patients with SYN had blunted increases in MSNA at low tilt levels, followed by a progressive decrease and ultimately complete disappearance of MSNA with syncope. SYN patients also had attenuation of norepinephrine increases and lower baroreflex slope sensitivity, both during tilt and after pharmacologic testing. FS+ subjects had the largest decrease in CVP with tilt and had significant increases in MSNA and heart rate baroreflex slopes. These data challenge the view that excessive generalized sympathetic activation is the precursor of the hemodynamic abnormality underlying recurrent neurally mediated syncope.

Vasopressin mediates the pressor effects of endothelin in the subfornical organ of the rat.

The potent vasoconstrictor peptide endothelin may affect central cardiovascular function in areas with incomplete blood-brain barrier such as the subfornical organ (SFO). In these studies, we determine whether microinjection of endothelin-1 (ET-1) into the SFO increases blood pressure (BP) in a dose-related manner and investigate the potential involvement of sympathetic and vasopressinergic mechanisms. In urethane-anesthetized Sprague-Dawley rats, BP was recorded intra-arterially, and ET-1 (0.125-6.0 pmol/60 nl) was microinjected stereotaxically into the SFO. Whereas vehicle (60 nl) did not change mean BP or HR, ET-1 evoked a dose-related pressor and bradycardic effect. The maximal changes were noted at the 1-pmol dose. No significant hemodynamic effects were observed with ET-1 microinjection in areas immediately surrounding the SFO or into the SFO of rats pretreated with a specific endothelin antagonist. In animals instrumented for recording of renal sympathetic nerve activity (RSNA), the administration of ET-1 (1 pmol/60 nl) evoked pressor (14 +/- 5 mm Hg) and bradycardic (-41 +/- 12 bpm) effects with a decrease in RSNA (16% +/- 3%). The effects on HR and RSNA seem to be mediated by baroreflex changes because in sino-aortic denervated rats, ET-1 pressor effects occur without inhibition of HR or RSNA. We documented the involvement of vasopressin in ET-1 actions by using vasopressin antagonists that inhibited the effects evoked by ET-1 administration. In addition, increases in vasopressin plasma levels were demonstrated at the time of the maximal effect of this peptide. These results indicate that ET-1 acting in the SFO increases BP by a vasopressinergic mechanism.

Cardiovascular effects of endothelin injected into brain nuclei regulating vasopressin release.

We studied the cardiovascular effects produced by administration of endothelin-1 (ET-1) into brain nucleic known to affect vasopressin release. In urethane-anesthetized Sprague-Dawley rats, microinjection of ET-1 into the subfornical organ (SFO) resulted in a dose-dependent increase in arterial blood pressure and a decrease in heart rate. These effects were inhibited by previous administration of the ETA receptor antagonist BQ-123 or by intravenous administration of a vasopressin antagonist. In addition, microinjection of ET-1 into the SFO increased plasma levels of vasopressin. In contrast, in the paraventricular nucleus (PVN) of the hypothalamus microinjection of ET-1 evoked a dose-related bradycardia with inconsistent changes in blood pressure. Although the bradycardia was antagonized by intra-PVN administration of BQ-123, the vasopressin antagonist did not affect the changes in heart rate evoked by microinjection of this peptide into the PVN. Overall, these results indicate that the central cardiovascular effects of ET-1 result from activation of several mechanisms, including stimulation of brain centers regulating vasopressin release.

[Efficacy and tolerance to acarbose in non-insulin-dependent diabetics]. / Eficacia y tolerancia de acarbose en pacientes diabéticos no dependientes de insulina.

Oral acarbose, a competitive inhibitor of alpha-glucosidase, has been shown to be effective in decreasing the postprandial rise in blood glucose and insulin. A double blind, cross-over, placebo controlled, randomized study in poorly controlled, non-insulin dependent diabetic patients under treatment with sulfonylureas was carried out. The patients continued receiving sulfonylureas throughout the study period and were randomly allocated into two sequences. In sequence A they received 100 mg tablets tid during 12 weeks; placebo tid during 2 weeks (wash-out period) and finally they were crossed over to placebo tid during 12 weeks. In sequence B, they received placebo tid 12 weeks, placebo tid during 2 weeks and finally acarbose 100 mg tid during 12 weeks. Sixteen patients were included in each sequence; three were excluded from sequence A, one because of side effects, one because of severe neuropathy and one because of change of address. One was excluded from sequence B because of failure to take the sulfonylurea. A slight but statistically significant decrease in weight was observed with acarbose as compared with placebo in both sequences. Significant reductions in postprandial glucose were observed in both sequences with acarbose. Significant reductions in fasting blood glucose were also observed in some visits. Although lower mean values of triglycerides and HbA1c were observed with acarbose, they were not statistically significant. Acarbose had side effects almost in all patients, but decreased on continued therapy. Only one patient had to be excluded for this cause. Acarbose is a useful therapeutic resource in poorly controlled non-insulin dependent diabetic patients in combination with sulfonylureas.

[Role of computerized tomography in Poland syndrome]. / Il ruolo della tomografia computerizzata nella sindrome di Poland.

A morphological CT study in Poland syndrome is presented. The osteomuscular anomalies of the chest, which are not demonstrated by usual x-Ray, are well defined by CT scans. The usefulness of CT in postoperative controls of muscles transfers is stressed.

[Fibromatosis of the mesenterium]. / Fibromatosi del mesentere.

A rare case of mesenteric fibromatosis observed in a 58 year old woman, repeatedly operated in the abdominal area, with a mesogastric-hypochondriac hard-elastic mass, is presented. Being the cause of the affection still unknown, an abnormal proliferation of fibrous tissue induced from chemical-physical injuries is considered at the basis of the clinical entity.

[Dosimetric study in vivo, using a computer, of Co-60 irradiation of patients with breast prosthesis made of silicone]. / Studio dosimetrico in vivo e a calcolatore di irradiazioni con 60Co di protesi mammarie in silicone.

This work studies the dose distribution through the chest wall in radiation therapy after mammary reconstruction with silicone prostheses. TLD experimental dosimetry has been done on patient with silicone prostheses, on patient without prostheses and on Alderson phantom. Various conditions of treatment have been theorically simulated on a computer. At least authors show the results evaluating the dose distribution through the chest wall, the skin and the local complications.

[Transduodenal papillosphincteroplasty]. / La papillo-sfintero-plastica transduodenale.

On the basis of a thourough anatomosurgical study of Vater's ampulla and after a critical survey of all surgical techniques for the sphincter of Oddi, the indications for and technique of total papillosphincteroplasty are presented. The results obtained in 544 total papillosphincteroplasties, their possible complications and failure supported by long-term (from 6 months to 7 years) follow-up are discussed. The conclusion is drawn that papillosphincteroplasty is to be considered the surgical technique of choice in the treatment of benign pathology of the main bile way.