Oral Delivery of Glucagon-Like Peptide-1 and Analogs: Alternatives for Diabetes Control?

Type 2 diabetes mellitus (T2DM) is one of the most prevalent diseases worldwide. Current treatments are often associated with off-target effects and do not significantly impact disease progression. New therapies are therefore urgently needed to overcome this social burden. Glucagon-like peptide-1 (GLP-1), an incretin hormone, has been used to control T2DM symptomatology. However, the administration of peptide or proteins drugs is still a huge challenge in the pharmaceutical field, requiring administration by parenteral routes. This article reviews the main hurdles in oral administration of GLP-1 and focuses on the strategies utilized to overcome them.     

Morphologic course of the left ventricle after renal transplantation. Echocardiographic study

OBJECTIVE: To characterize and to quantitate the morphologic changes in left ventricle, in renal transplant patients (Pts) treated with cyclosporine, through sequential echocardiographic examinations. DESIGN: A prospective study of renal transplant patients, between October/88 and May/89, who maintained good function of the renal graft during the follow-up. SETTING: Cardiology and Nephrology departments of Santo António Hospital. MATERIAL AND METHODS: 20 patients, 13 men and 7 women, mean age of 33 +/- 10, ranging from 20 to 56, constitute the final group of the study. These patients have been receiving dialysis during 3.8 +/- 2.3 years (0.4-8). Seven patients were excluded, five by echocardiographic criteria and another two because of chronic renal graft disfunction (creatinine greater than 2.0 mg%). The echocardiographic examinations were performed during the first week, and 1, 2, 3, 6 and 12 months after renal transplantation. The following measurements were performed: left ventricular end-diastole diameter (LVED), interventricular septal thickness (IVST), posterior wall thickness (PWT) and left ventricular mass index (LVMI). The measurements were obtained in M-mode following the conventional recommendations. Average values of at least 3 cardiac cycles were used. Heart rate, blood pressure, creatinine, hematocrit, body surface area and fistula patency, were determined at the time of each echocardiogram. MAIN RESULTS: The LVED decreased progressively until the third month, from 51.9 +/- 7 mm to 47.8 +/- 6 mm (p less than 0.001), remaining stable thereafter. The baseline value of IVST, 13.6 +/- 5 mm, was similar at the twelfth month, 13.8 +/- 2 mm (ns). The baseline value of PWT, 13.7 +/- 4 mm, decreased gradually since the second month, having reached 12.7 +/- 2 mm at the twelfth month (ns). The LVMI (g/m2) reduced progressively, from 243 +/- 82 to 190 +/- 38 at the end of the study (p less than 0.05. A high incidence of arterial hypertension was detected during the follow-up period; at the twelfth month, 18 patients (90%) were on antihypertensive drug therapy, 11 of which had blood pressure greater than or equal to 160/95 mmHg. CONCLUSIONS: We verified, one year after the renal transplantation, a significant decrease of LVMI, that was mainly determined by the LVED reduction. Left ventricular walls thickness had no significant variation; we think that the high incidence of hypertension during the follow-up period, in part due to the pressure effect of cyclosporine, may have been responsible for this fact.     

Experimental Traumatic Cerebral Contusion: Morphological Study of Brain Microvessels and Characterization of the Oedema

Summary Several experimental brain oedema models are currently available, but most of them are very different from what happens in clinical practice. As it is simple and seems to replicate the range of injuries seen in man we decided to evaluate Marmarou's model of head injury in order to test physiopathogenic and therapeutic hypotheses. Three groups of Wistar rats weighing 360–400 gr, anaesthetized with sodium pentobarbitone and breathing spontaneously, without tracheal intubation, were studied. In the first group six animals were killed two hours after injury and the brain's water content compared with that of nine controls. In another group Evans blue (100 mg/kg) was injected one hour before trauma and dye's extraction ratio determined at various times after injury: five animals at 15 minutes, six at 30 minutes, five at 60 minutes and nine at 120 minutes. A total of twenty-eight animals served as controls. In the last group morphological studies with light and electron microscopy were performed in the traumatized brain tissue from rats killed 5 and 120 minutes after injury and in brain tissue from control rats. Results showed that Marmarou's brain trauma model induced perivascular brain oedema, already visible at the ultrastructural level 5 minutes after the injury. Endothelial cells themselves were “oedematiated”, rich in pinocytotic vesicles and membrane blebs, and presented intact tight junctions. Two hours after trauma the perivascular oedema was more marked. At this time the brain water content was significantly higher than that in controls. Evans blue extraction ratio increased linearly with time, being significantly higher than in controls 120 minutes after injury. We conclude that Marmarou's model is a suitable model for the study of brain oedema induced by trauma, and that this oedema, assessed by three different methodologies, was statistically significant two hours after injury.     

Impact of homocysteinemia on long-term renal transplant survival

AIM: We prospectively followed a cohort of 202 renal transplant recipients for 5 years to examine the impact of fasting homocysteinemia on long-term patient and renal allograft survival. METHODS: Cox proportional hazards regression analysis was used to identify independent predictors of all-cause mortality and graft loss. RESULTS: Hyperhomocysteinemia (tHcy >15 micromol/L) was present in 48.7% of the 202 patients, predominantly among men (55.8%) as opposed to women (37.1%). At the end of the follow-up period, 13 (6.4%) patients had died including 10 from cardiovascular disease, and 23 had (11.4%) had lost their grafts. Patient death with a functioning allograft was the most prevalent cause of graft loss (13 recipients). Levels of tHcy were higher among patients who died than among survivors (median 23.9 vs 14.3 micromol/L; P = .005). Median tHcy concentration was also higher among the patients who had lost their allografts than those who did not (median 19.0 vs 14.1 micromol/L; P = .001). In a Cox regression model including gender, serum creatinine concentration, transplant duration, traditional cardiovascular risk factors, and associated conditions, such as past cardiovascular disease, only tHcy concentration (ln) (HR = 5.50; 95% CI, 1.56 to 19.36; P = .008) and age at transplantation (HR = 1.07; 95% CI, 1.02 to 1.13; P = .01) were independent predictors of patient survival. After censoring data for patient death, tHcy concentration was not a risk factor for graft loss. CONCLUSIONS: This prospective study shows that tHcy concentration is a significant predictor of mortality, but not of graft loss, after censoring data for patient death.     

Impact of antihelminthic treatment on infection by Ascaris lumbricoides, Trichuris trichiura and hookworms in Covas, a rural community of Pernambuco, Brazil

This work aims to evaluate the impact of drug treatment on infection by Ascaris lumbricoides (Al), Trichuris trichiura (Tt) and hookworms (Hook) in a rural community from the sugar-cane zone of Pernambuco, Brazil. Four parasitological surveys were carried out from March 2001 to March 2002. Individual diagnosis was based on eight slides (four by the Kato-Katz method and four by the Hoffman method) per survey. Infected subjects were assigned to two groups for treatment with either albendazole (n = 62) or mebendazole (n = 57). Prevalence of infection fell significantly (p < 0.05) one month after treatment: Al (from 47.7% to 6.6%); Tt (from 45.7% to 31.8%) and Hook (from 47.7% to 24.5%). One year after treatment, infections by Tt and Hook remained significantly below pre-control levels. A substantial decrease in single-infection cases and multiple infections was found. Egg-negative rate was significant for Al (94.0%), Hook (68.3%) but not for Tt (45.5%), and did not differ significantly between subjects treated with mebendazole or albendazole. Egg counts fell significantly in the individuals remaining positive for Tt. It is recommended that antihelminthic treatment should be selective and given at yearly intervals preferably with albendazole, due to its cost-effectiveness.     

Age as an independent risk factor for secondary headaches

OBJECTIVE: To verify if the age is a risk factor for secondary headaches, regardless the time interval since the onset of the headache complaint. METHOD: 1131 patients were selected, with the main complaint of headache. The ratio of secondary headaches was evaluated and compared between young and elderly patients in general; between individuals with headache starting before and after 60 years of age; and between young and elderly subjects with headache having started for less than one year. RESULTS: Elderly patients in general and individuals with headache having started after 60 years of age presented a higher ratio of secondary headaches than the young subjects and the ones whose pain started before 60 years of age. Elderly subjects with headache of recent start presented a higher ratio of secondary headaches than young individuals with the same time of pain evolution. CONCLUSION: Age is an independent risk factor for secondary headaches, regardless the time interval since the onset of the complaint.