Judith A.E. Somers

Lack of effect of the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig

1 In anaesthetized animals, the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine, reduce carotid arteriovenous anastomotic shunting. Within the carotid vascular bed arteriovenous anastomoses are located, amongst other places in the dura mater, which is a putative site of the pain during a migraine attack. 2 In this investigation, we have localized and measured the arteriovenous shunting within the carotid vascular bed of the pig by using simultaneous intracarotid injections of radiolabelled microspheres of three different sizes (10, 15 and 50 μm), which provides an index of blood flow via arteriovenous anastomoses larger than approximately 14, 27 and 90 μm diameter, respectively. The effects of sumatriptan (0.3 mg kg−1), ergotamine (0.02 mg kg−1), dihydroergotamine (0.1 mg kg−1) and saline were studied by repeating the injections of 15 and 50 μm spheres after the treatments. 3 There was no difference in shunting or entrapment between the 10 and 15 μm microsphere, indicating the absence of arteriovenous anastomoses with a diameter between 14 and 27 μm. 4 Arteriovenous anastomoses with a diameter between 27 and 90 μm, as indicated by the difference in blood flow measured by 15 and 50 μm spheres, were located in the dura mater, ears, skin, fat and, to a lesser extent, in the skeletal muscles and eyes. 5 Sumatriptan, ergotamine and dihydroergotamine reduced the overall flow in the smaller arteriovenous anastomoses (diameter between 27 and 90 μm), and even more in larger shunts (wider than 90 μm). 6 Locally, blood flow in the smaller arteriovenous shunts was reduced in the skin and fat, but not in the dura mater, ears, eyes and muscles. It is not possible to determine in which tissues blood flow in the larger arteriovenous anastomoses was reduced. 7 Tissue blood flow measured with 15 μm microspheres remained unchanged after the three antimigraine drugs, implying a lack of effect on capillary flow. 8 It is concluded that in the anaesthetized pigs the only evident effect of these antimigraine drugs on carotid haemodynamics is a decrease in blood flow in both smaller and larger arteriovenous anastomoses; the smaller arteriovenous anastomoses were affected in the skin and fat, but not in other tissues.

Comparative effects of the antimigraine drugs sumatriptan and ergotamine on the distribution of cardiac output in anaesthetized pigs

The haemodynamic effects of sumatriptan, a 5-HT 1 -like receptor agonist, and ergotamine, an agonist at a-adrenergic, dopamine as well as 5-HT receptors, were compared using intracardiac injection of radioactive microspheres of different sizes in anaesthetized pigs. Ergotamine (0.02 mg-kg-1 ) and sumatriptan (0.3 mg. kg-1 ) decreased systemic vascular conductance and cardiac output. Only ergo-famine raised arterial blood pressure. Both sumatriptan and ergotamine decreased arteriovenous anastomotic, but not capillary, blood flow in the head and body skin. Arteriovenous and capillary blood flow in the dura mater and nasal mucosa and capillary blood flow in the brain, kidneys, adrenals, intestine, heart, spleen and muscle remained unchanged. However, kidney conductance was decreased by both drugs, spleen conductance by sumatriptan and heart, liver and adrenal conductances were decreased by ergotamine. Thus, both sumatriptan and ergotamine constricted arteriovenous anastomoses in the skin, but not in the dura mater or nasal mucosa. Ergotamine constricted the vasculature more than sumatriptan, although both drugs may differentially decrease vascular conductances in some organs.

Rapid induction of single donor chimerism after double umbilical cord blood transplantation preceded by reduced intensity conditioning: results of the HOVON 106 phase II study

Double umbilical cord blood transplantation is increasingly applied in the treatment of adult patients with high-risk hematological malignancies and has been associated with improved engraftment as compared to that provided by single unit cord blood transplantation. The mechanism of improved engraftment is, however, still incompletely understood as only one unit survives. In this multicenter phase II study we evaluated engraftment, early chimerism, recovery of different cell lineages and transplant outcome in 53 patients who underwent double cord blood transplantation preceded by a reduced intensity conditioning regimen. Primary graft failure occurred in one patient. Engraftment was observed in 92% of patients with a median time to neutrophil recovery of 36 days (range, 15–102). Ultimate single donor chimerism was established in 94% of patients. Unit predominance occurred by day 11 after transplantation and early CD4+ T-cell chimerism predicted for unit survival. Total nucleated cell viability was also associated with unit survival. With a median follow up of 35 months (range, 10–51), the cumulative incidence of relapse and non-relapse mortality rate at 2 years were 39% and 19%, respectively. Progressionfree survival and overall survival rates at 2 years were 42% (95% confidence interval, 28–56) and 57% (95% confidence interval, 43–70), respectively. Double umbilical cord blood transplantation preceded by a reduced intensity conditioning regimen using cyclophosphamide/fludarabine/4 Gy total body irradiation results in a high engraftment rate with low non-relapse mortality. Moreover, prediction of unit survival by early CD4+ lymphocyte chimerism might suggest a role for CD4+ lymphocyte mediated unit-versus-unit alloreactivity. www.trialregister.nl NTR1573.

Impaired thymopoiesis predicts for a high risk of severe infections after reduced intensity conditioning without anti-thymocyte globulin in double umbilical cord blood transplantation

Umbilical cord blood stem cell transplantation (UCBT) is associated with retarded hematopoietic recovery and immune reconstitution and a high infection-related morbidity and mortality, especially after conditioning including anti-thymocyte globulin (ATG). However, data on immune recovery, incidence of infections, and outcome in double UCBT (dUCBT) recipients receiving an ATG-free reduced intensity conditioning (RIC) are lacking. In this study, recovery of lymphocyte subsets, thymopoiesis, and its association with severe infections and clinical outcome was assessed in a group of 55 recipients of a dUCBT ATG-free RIC regimen. T cell recovery was severely protracted in the majority of patients. However, T cell receptor excision circle TREC+ T cells were detectable in 62% of patients at 3 months post-transplantation. A total of 128 common toxicity criteria grade 3−4 infections were observed in the first year post-transplantation. Non-relapse mortality at 12 months post-transplant was 16%, of which 78% infectious mortality. One-year overall survival was 73%. Patients who failed to recover thymopoiesis at 3 months post-transplantation were at a 3.3-fold higher risk of subsequent severe grade 3–4 infections.