Cranial circulatory effects of antimigraine drugs: an experimental study in the pig

This thesis is main! y concerned with an investigation in anaesthetized pigs of the vascular effects of sumatriptan, ergotamine and dihydroergotamine, drugs used in the treatment of the acute migraine attack. There are several reasons for performing this investigation. Firstly, a disturbance within the cranial blood vessels has long been implicated in the pathogenesis of migraine. Such a vascular theory was first mentioned in 1684 by Thomas Willis, following the discovery of the blood circulation by Harvey. Until the middle of this century, an experimental basis for the vascular theory lacked, but it was strengthened by the experiments of Graham & Wolff (1938), who demonstrated increased pulsations of the superficial temporal artery in a proportion of their patients. More recently the primarily vascular theory has been severely criticized by many researchers in the field and a primarily neurological theory has been adopted. This theory involves hyperactivity of the pain-conducting trigeminal nerve, leading to pain, but also dilatation of the blood vessels innervated by this nerve (Markowitz eta!., 1988). Therefore, even the leading neurological theory of this moment implies vascular involvement in the migraine attack, even if not the primary cause. Secondly the antimigraine drugs mentioned above are powerful vasoactive agents. They usually constrict the carotid blood vessels, especially when they had been dilated before (Saxena & De Vlaam-Schluter, 1974). It is, therefore, quite possible that a vasoconstrictor action of these drugs contributes to the antimigraine activity. On the other hand, it is now proposed, albeit not yet definitely proven, that a direct effect of these drugs on the trigeminal nerve innervating the dura mater is a factor in their antimigraine efficacy (Markowitz et aL, 1988; Buzzi & Moskowitz, 1990). A direct vascular action could, however, even explain the effects of these drugs on the dura mater. It is not known which blood vessels are mainly involved in migraine. The pharmacological profile of the antimigraine drugs could provide a clue. The fact that they are potent constrictors of arteries and arteriovenous anastomoses, but not of arterioles (Miiller-Schweinitzer & Weidmann, 1978; Saxena, 1978; this thesis) could point to involvement of arteries or arteriovenous anastomoses in migraine. For both some experimental evidence is present (Heyck, 1969; Friberg eta!., 1991) The present thesis is aimed at contributing to the knowledge of the vascular pharmacologic profile of these antimigraine drugs. The effect of these drugs on arteriovenous anastomoses and arterioles both in the head and in the body (the effect on arteries is beyond the scope of this thesis) was determined with injection of radioactive microspheres in anaesthetized pigs. Furthermore, by use of suitable pharmacologic agents an attempt was made to characterize the receptors involved in these vascular effects. By a good pharmacological characterization it might, in future, be possible to develop more specific antimigraine agents. Lastly, an attempt was made to determine the neurotransmitter which may be responsible for the tonic contraction of the arteriovenous anastomoses. Before the presentation of the results of this investigation, chapters 2 through 4 will discuss in detail the field on which this thesis is based. In chapter 2 current views on the pathophysiology of migraine will be discussed. Chapter 3 is concerned with previous knowledge on the pharmacology of the antimigraine agents. In chapter 4 general features of the cranial circulation are discussed, with the existing differences between the human and porcine circulations. Chapter 6 will specify the aim of the thesis

NG-nitro L-arginine methyl ester: systemic and pulmonary haemodynamics, tissue blood flow and arteriovenous shunting in the pig

The effects of NG-nitro-Lrarginine methyl ester (L-NAME), an inhibitor of the endothelial nitric oxide (NO) biosynthesis, on systemic and pulmonary haemodynamics, and tissue as well as arteriovenous anastomotic blood flows were investigated in the anaesthetized pig, using simultaneous injections of radioactive microspheres of two different sizes (diameter: 15 and 50μm). L-NAME (1, 3 and 10 mg·kg-1) reduced systemic and pulmonary artery conductance and cardiac output, but heart rate and mean arterial blood pressure remained unchanged. L-arginine reversed the systemic and pulmonary haemodynamic changes induced by L-NAME. As detected with 15 μm microspheres, L-NAME (1 and 3 mg·kg-1) decreased tissue blood flow to and vascular conductance in the eyes, lungs, atria, kidneys, adrenals and liver. Furthermore, the difference between blood flows simultaneously measured with 15 and 50 μm microspheres, which can be equated to blood flow through arteriovenous anastomoses with a diameter between about 28 and 90 μm, was reduced by L-NAME (3 mg · kg-1) in the skin of head and gluteal regions and, as indicated by the microsphere content of the lungs, in the total systemic circulation. These results suggest that in the anaesthetized pig (i) NO is involved in the regulation of both systemic and pulmonary vascular conductance, (ii) the decrease in systemic vascular conductance is in part due to constriction of systemic arteriovenous anastomoses, and (iii) the decrease in pulmonary vascular conductance, leading to reduction of cardiac output, seems to negate the expected rise in arterial blood pressure observed, for example, in rats and rabbits following inhibition of NO-synthesis

Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer

PURPOSE: To investigate the toxicity of nelfinavir, administered during preoperative chemoradiotherapy (CRT) in patients with locally advanced cancer. MATERIAL AND METHODS: Twelve patients were treated with to 50.4Gy combined with capecitabine 825mg/m2 BID. Three dose levels nelfinavir were tested: 750mg BID (DL1), 1250mg BID (DL2) and an level of 1000mg BID (DL3). Surgery was performed between 8 and 10weeks completion of CRT. Primary endpoint was dose-limiting toxicity (DLT), any grade 3 or higher non-hematological or grade 4 or higher toxicity. RESULTS: Eleven patients could be analyzed: 5 were treated in DL2 and 3 in DL3. The first 3 patients in DL1 did not develop a DLT. In patient developed gr 3 diarrhea, 1 patient had gr 3 transaminase patient had a gr 3 cholangitis with unknown cause. An intermediate dose tested in DL3. In this group 2 patients developed gr 3 diarrhea and 1 3 transaminase elevation and gr 4 post-operative wound complication. patients achieved a pathological complete response (pCR). CONCLUSIONS: 750mg BID was defined as the recommended phase II dose in combination capecitabine and 50.4Gy pre-operative radiotherapy in rectal cancer. response evaluations are promising, but a further phase II study is more information about efficacy of this treatment regimen

Variability of cost trajectories over the last year of life in patients with advanced breast cancer in the Netherlands

Objective In breast cancer patients, treatment at the end of life accounts for a major share of medical spending. However, little is known about the variability of cost trajectories between patients. This study aims to identify underlying latent groups of advanced breast cancer patients with similar cost trajectories over the last year before death. Methods Data from deceased advanced breast cancer patients, diagnosed between 2010 and 2017, were retrieved from the Southeast Netherlands Advanced Breast Cancer (SONABRE) Registry. Costs of hospital care over the last twelve months before death were analyzed, and the variability of longitudinal patterns between patients were explored using group-based trajectory modeling. Descriptive statistics and multinomial logistic regression were applied to investigate differences between the identified latent groups. Results We included 558 patients. Over the last twelve months before death, mean hospital costs were €2,255 (SD = €492) per month. Costs increased over the last five months and reached a maximum of €3,614 in the last month of life, driven by hospital admissions, while spending for medication declined over the last three months of life. Based on patients’ individual cost trajectories, we identified six latent groups with distinct longitudinal patterns, of which only two showed a marked increase in costs over the last twelve months before death. Latent groups were constituted of heterogeneous patients, and clinical characteristics explained membership only to a limited extent. Conclusions The average costs of advanced breast cancer patients increased towards the end of life. However, we uncovered several latent groups of patients with divergent cost trajectories, which did not reflect the overall increasing trend. The mechanisms underlying the variability in cost trajectories warrants further research

Clinical characteristics of women captured by extending the definition of severe postpartum haemorrhage with 'refractoriness to treatment': a cohort study

Background: The absence of a uniform and clinically relevant definition of severe postpartum haemorrhage hampers comparative studies and optimization of clinical management. The concept of persistent postpartum haemorrhage, based on refractoriness to initial first-line treatment, was proposed as an alternative to common definitions that are either based on estimations of blood loss or transfused units of packed red blood cells (RBC). We compared characteristics and outcomes of women with severe postpartum haemorrhage captured by these three types of definitions. Methods: In this large retrospective cohort study in 61 hospitals in the Netherlands we included 1391 consecutive women with postpartum haemorrhage who received either ≥4 units of RBC or a multicomponent transfusion. Clinical characteristics and outcomes of women with severe postpartum haemorrhage defined as persistent postpartum haemorrhage were compared to definitions based on estimated blood loss or transfused units of RBC within 24 h following birth. Adverse maternal outcome was a composite of maternal mortality, hysterectomy, arterial embolisation and intensive care unit admission. Results: One thousand two hundred sixty out of 1391 women (90.6%) with postpartum haemorrhage fulfilled the definition of persistent postpartum haemorrhage. The majority, 820/1260 (65.1%), fulfilled this definition within 1 h following birth, compared to 819/1391 (58.7%) applying the definition of ≥1 L blood loss and 37/845 (4.4%) applying the definition of ≥4 units of RBC. The definition persistent postpartum haemorrhage captured 430/471 adverse maternal outcomes (91.3%), compared to 471/471 (100%) for ≥1 L blood loss and 383/471 (81.3%) for ≥4 units of RBC. Persistent postpartum haemorrhage did not capture all adverse outcomes because of missing data on timing of initial, first-line treatment. Conclusion: The definition persistent postpartum haemo

Plasma biomarker analysis in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC) treated with first-line bevacizumab (A) and paclitaxel (T) without or with capecitabine (X)

Experimentele farmacotherapi

Genetic polymorphisms (SNPs) as predictive markers for paclitaxel-induced peripheral neuropathy (PNP) and capecitabine-induced hand-foot syndrome (HFS) in HER-2 negative metastatic breast cancer patients

Experimentele farmacotherapi

Perceptions of involvement in advance care planning and emotional functioning in patients with advanced cancer

Contains fulltext : 235043.pdf (Publisher’s version ) (Open Access)PURPOSE: Advance Care Planning (ACP) is positively associated with the quality of care, but its impact on emotional functioning is ambiguous. This study investigated the association between perceptions of ACP involvement and emotional functioning in patients with advanced cancer. METHODS: This study analyzed baseline data of 1,001 patients of the eQuiPe study, a prospective, longitudinal, multicenter, observational study on quality of care and quality of life in patients with advanced cancer in the Netherlands. Patients with metastatic solid cancer were asked to participate between November 2017 and January 2020. Patients' perceptions of ACP involvement were measured by three self-administered statements. Emotional functioning was measured by the EORTC-QLQ-C30. A linear multivariable regression analysis was performed while taking gender, age, migrant background, education, marital status, and symptom burden into account. RESULTS: The majority of patients (87%) reported that they were as much involved as they wanted to be in decisions about their future medical treatment and care. Most patients felt that their relatives (81%) and physicians (75%) were familiar with their preferences for future medical treatment and care. A positive association was found between patients' perceptions of ACP involvement and their emotional functioning (b=0.162, p<0.001, 95%CI[0.095;0.229]) while controlling for relevant confounders. CONCLUSIONS: Perceptions of involvement in ACP are positively associated with emotional functioning in patients with advanced cancer. Future studies are needed to further investigate the effect of ACP on emotional functioning. TRIAL REGISTRATION NUMBER: NTR6584 Date of registration: 30 June 2017 IMPLICATIONS FOR CANCER SURVIVORS: Patients' emotional functioning might improve from routine discussions regarding goals of future care. Therefore, integration of ACP into palliative might be promising