Metoclopramide as an analgesic in severe migraine attacks: an open, single-blind, parallel control study

Metoclopramide is a well-known anti-emetic drug with central and peripheral pharmacological effects. Some authors have reported metoclopramide as an adjunct therapy to other analgesics in patients with migraine attacks. Treatment of migraine headache using a mix of metoclopramide and an NSAID has been patented (European Patent EP1014961) as well as a short series showing great efficacy and tolerability of metoclopramide in patients wtih migraine attacks. We decided to conduct an open, single-blind, parallel control study in the emergency department to evaluate the efficacy and tolerability of metoclopramide in patients with severe migraine attacks. 93 consecutive patients with severe migraine attacks were randomized into two groups (groups A and B). Patients in group A received 10mg of intravenous metoclopramide and patients in group B received 1 g of intravenous paracetamol. Patients were evaluated 5 minutes before (baseline), 15, 30, 60 and 120 minutes after drug delivery, and before being discharged from the emergency department They were then contacted by phone 48 hours after being discharged from the hospital (phone questionnaire). Patients treated with either metoclopramide or paracetamol showed a significant reduction in the intensity of pain at the 120 minute time point, with an 86% and 82% improvement respectively. However, patients treated with metoclopramide showed a more rapid improvement at the 15 and 30 minute evaluations. Patients with severe migraine attacks treated with metoclopramide as monotherapy showed a significant improvement in terms of pain relief and a faster improvement in pain intensity compared to those treated with paracetamol. Metoclopramide and other dopamine antagonistic drugs should be considered a therapeutic option in severe migraine headache attacks.     

Sleep complaints in community-living older persons: a multifactorial geriatric syndrome

In older persons, sleep complaints in the form of insomnia and daytime drowsiness are highly prevalent and are associated with adverse outcomes. The underlying mechanisms are linked to age-related declines in physiology (normal aging) and age-related increases in disease prevalence (usual aging). This article describes how normal aging leads to less-restorative sleep, characterized by reductions in homeostatic and circadian sleep, and to phase advancement of the sleep–wake cycle, characterized by older persons being more alert in the early morning but drowsier in the early evening. It also describes how usual aging leads to sleep complaints through reductions in health status, loss of physical function, and primary sleep disorders. Psychosocial influences are likewise described, and their relevance to sleep complaints is discussed. These aging-related changes are subsequently incorporated into a conceptual model that describes sleep complaints as a consequence of multiple and interdependent predisposing, precipitating, and perpetuating factors, akin to a geriatric syndrome. The discussion concludes by applying the conceptual model to the sleep-related care of an older person with insomnia and daytime drowsiness and suggesting that the diagnostic assessment consider, in addition to primary sleep disorders, multiple domains, including medical, physical, cognitive, psychological, and social matters, with the intent of developing an overall therapeutic plan and establishing long-term follow-up.     

Mesenchymal stem cells secreting angiopoietin-like-5 support efficient expansion of human hematopoietic stem cells without compromising their repopulating potential

Clinical and preclinical applications of human hematopoietic stem cells (HSCs) are often limited by scarcity of cells. Expanding human HSCs to increase their numbers while maintaining their stem cell properties has therefore become an important area of research. Here, we report a robust HSC coculture system wherein cord blood CD34(+) CD133(+) cells were cocultured with mesenchymal stem cells engineered to express angiopoietin-like-5 in a defined medium. After 11 days of culture, SCID repopulating cells were expanded ~60-fold by limiting dilution assay in NOD-scid Il2rg(-/-) (NSG) mice. The cultured CD34(+) CD133(+) cells had similar engraftment potential to uncultured CD34(+) CD133(+) cells in competitive repopulation assays and were capable of efficient secondary reconstitution. Further, the expanded cells supported a robust multilineage reconstitution of human blood cells in NSG recipient mice, including a more efficient T-cell reconstitution. These results demonstrate that the expanded CD34(+) CD133(+) cells maintain both short-term and long-term HSC activities. To our knowledge, this ~60-fold expansion of SCID repopulating cells is the best expansion of human HSCs reported to date. Further development of this coculture method for expanding human HSCs for clinical and preclinical applications is therefore warranted.     

The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH-dependent Cushing's syndrome

OBJECTIVE: Bilateral inferior petrosal sinus sampling (BIPSS) with corticotrophin-releasing hormone (CRH) stimulation is currently the gold standard test for the differential diagnosis of ACTH-dependent Cushing's syndrome. Reports on the use of desmopressin in this approach are limited. The aim of this study was to evaluate the use of desmopressin during BIPSS in a cohort of patients with ACTH-dependent Cushing's syndrome. DESIGN: A retrospective case-record study. PATIENTS: Fifty-six patients with confirmed ACTH-dependent Cushing's syndrome underwent BIPSS with desmopressin stimulation when presenting negative pituitary tumour imaging. MEASUREMENTS: Central to peripheral (CEN:PER) ACTH gradient, lateralization of the ACTH source and surgical tumour confirmation were evaluated. RESULTS: A CEN:PER ACTH gradient was found in 40 patients under basal conditions (CEN:PER >or= 2) and in 47 patients after desmopressin stimulation (CEN:PER >or= 3). Ectopic ACTH-producing tumours (three lung carcinoid tumour, one thymus carcinoid tumour and one thymus hyperplasia) were confirmed in five out of nine patients without the CEN:PER ACTH gradient, and four cases were false negative for Cushing's disease. Lateralization (IPS:IPS >or= 1.4) was observed in 80.8% of patients under basal conditions (38/47) and in 97.8% after desmopressin (46/47), and it was surgically confirmed in 78.7%. There were no false-positive cases. Sensitivity and specificity were 92.1% and 100%, respectively. CONCLUSIONS: Desmopressin improves the differential diagnosis of ACTH-dependent Cushing's syndrome by amplifying the CEN:PER and IPS:IPS ACTH gradients, and is therefore a useful ACTH secretagogue in BIPSS.     

The positive effects of a physical activity program for multiple sclerosis patients with fatigue

Fatigue is a common and disabling symptom of multiple sclerosis (MS). There is no effective pharmacological treatment for fatigue, although a few reports point towards beneficial effects from physical activity for MS patients suffering from fatigue. We devised a physical activity program for MS patients with fatigue and present the results from our first use of this program, on nine patients from our region. The program consisted of a 20-week series of gradual stretching, resistance and aerobic exercises, adapted to the individual clinical condition of each patient. The results showed significant improvement in cardio-circulatory parameters, as well as a significant decrease in scores on the fatigue scale. The success of this program led patients to ask to continue with it after the trial was finished, and more patients are enrolling in the program, motivated by the good results reported by fellow patients.     

Design,synthesis, antileishmanial,and antifungal biological evaluation of novel 3,5-disubstituted isoxazole compounds based on 5-nitrofuran scaffolds

Nineteen 3,5-disubstituted-isoxazole analogs were synthesized based on nitrofuran scaffolds, by a [3 + 2] cycloaddition reaction between terminal acetylenes and 5-nitrofuran chloro-oxime. The compounds were obtained in moderate to very good yields (45–91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p–r were active on both the promastigote and amastigote forms, with emphasis on compound 14p , which showed strong activity against the amastigote form (IC₅₀ = 0.6 μM and selectivity index [SI] = 5.2). In the alkyl series, compound 14o stands out with an IC₅₀ = 8.5 μM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron-donor groups, such as trimethoxy isoxazole 14g (IC₅₀ = 1.2 μM and SI = 20.2); compound 14h , with IC₅₀ = 7.0 μM and SI = 6.1; and compound 14j containing the 4-SCH₃ group, with IC₅₀ = 5.7 μM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration [MIC] = 3.4 μM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 μM for C. glabrata, lower than that of the fluconazole used as the reference drug.