Measures of Functioning in Patients With Episodic Migraine: Findings From a Double‐Blind,Randomized, Placebo‐Controlled Phase 2b Trial With Galcanezumab

Objective – To evaluate 12‐week changes from baseline of 2 disease‐specific patient‐reported outcome (PRO) measures in adults with migraine treated with galcanezumab, an investigational humanized antibody binding calcitonin gene‐related peptide (CGRP), or placebo. Background – Preventing headache‐related functional impairment is an important goal of migraine preventive treatment and a measurement target for PROs. Understanding which drugs have the potential to improve patient functioning in addition to preventing migraine headaches is vital to lessening patient burden. Design/Methods – This Phase 2b double‐blind, randomized, placebo‐controlled study enrolled adults with episodic migraine. Galcanezumab (120 mg subcutaneous injection; n = 60) or placebo (n = 127) was administered every 28 days for 12 weeks. Post hoc secondary analyses were conducted for those who completed 12 weeks of treatment on 2 PROs: The Migraine‐Specific Quality of Life Questionnaire (MSQ) v2.1 and the Headache Impact Test? (HIT‐6). Results – Analysis of covariance revealed significant differences in least square mean changes from baseline between galcanezumab and placebo for all MSQ domains including total mean change placebo of 18.63, galcanezumab of 27.36 (95% CI 2.449, 15.008; P‐value of .0067); Role Function‐Restrictive mean change placebo of 22.40, galcanezumab of 31.92 (95% CI 2.636, 16.518; P‐value of .0071); Role Function‐Preventive mean change placebo of 13.43, galcanezumab of 19.76 (95% CI 0.476, 12.185; P‐value of .0342); and Emotional Function mean change placebo of 16.88, galcanezumab of 26.61 (95% CI 2.789, 16.674; P‐value of .0063). At baseline, mean number of migraine headache days (MHDs) did not correlate with MSQ total scores or HIT‐6. At 12 weeks post‐treatment, MHD correlated with MSQ and HIT‐6 scores (all P < .0001). Change in MHD was associated with change in MSQ domains and change in HIT‐6 scores (all P < .0001). Conclusions – In comparison with placebo, treatment with galcanezumab was associated with significant functional improvements as reflected by changes in MSQ scores. Change in MHD was associated with improvements in MSQ and reductions in HIT‐6 scores, indicating the clinical importance of these changes in relation to PROs that measure function.     

Calcitonin-related peptides in patients with acute leukemia: association of human calcitonin with poor prognosis

Elevated serum levels of peptides hormones in patients with acute leukemia and production of these agents by the leukemic blasts have been described. In 77 patients with acute leukemia the influence of common risk factors and elevations of serum levels of calcitonin-related peptides on clinical outcome was evaluated. By multivariate analysis, only age and elevated serum level of h-CT were found to be significantly correlated to survival. CGRP and s-CT showed no influence on outcome. Closer inspection of the clinical course of these patients showed that patients with elevated h-CT are not likely to survive the first 4 weeks after diagnosis. The possibility that this hormone may influence the biological behavior of the leukemic cells is discussed.     

The role of CGRP and afferent nerves in the modulation of pancreatic enzyme secretion in the rat

Summary Conclusion Stimulation of pancreatic sensory nerves by capsaicin produced secretory effects probably caused, at least in part, by the release of CGRP. Background In the pancreas calcitonin gene-related peptide (CGRP) has been localized in the sensory nerves, but its physiological role is unknown. This study was undertaken to compare the changes of pancreatic enzyme secretion produced by CGRP and by stimulation or destruction of sensory nerves. Methods To stimulate sensory nerves, low doses of capsaicin (0.25–0.5 mg/kg) were given intraduodenally to the conscious rats with chronic pancreatic fistula. To inactivate sensory nerves high doses of capsaicin (100 mg/kg) were given subcutaneously 10 d before tests. For the in vitro experiments pancreatic slices and isolated pancreatic acini were prepared from intact and capsaicin-denervated rats. Results In conscious rats, CGRP given subcutaneously (5–10 μg/kg) and low doses of capsaicin given intraduodenally reduced basal pancreatic secretion. In isolated pancreatic acini, CGRP (10⁻¹⁰–10⁻⁶ M), but not capsaicin, increased basal or secretagog-stimulated amylase release. In pancreatic slices (containing nerve fibers) capsaicin (10⁻¹⁰–10⁻⁶ M) increased enzyme secretion, and this secretion was abolished by previous inactivation of sensory nerves by this neurotoxin. Capsaicin deactivation did not affect the secretory response of pancreatic acini to CGRP, cerulein, or urecholine. Sensory denervation by capsaicin did not change basal protein secretion, but reduced that produced by feeding or diversion of pancreatic juice to the exterior during first 2 h of the tests.     

Oxygen toxicity in the infant rhesus monkey: effects on regulatory peptides in lung and blood

A total of ten 6-month-old male rhesus monkey (Macaca mulatta) infants, born full-term, were positive-pressure ventilated with greater than 95% oxygen or room air (controls). A protocol was used which closely simulated pediatric intensive care. To test if regulatory peptides were affected by the oxygen treatment, and to search for an early marker of oxygen toxicity, lung tissue samples and systemic mixed venous blood were collected at 6, 12 and 24 hours after onset of treatment. The peptides, gastrin releasing peptide (GRP), calcitonin gene-related peptide (CGRP), peptide YY (PYY), vasoactive intestinal peptide (VIP) and somatostatin (SOM), were quantitated in lung tissue extracts and plasma using radioimmunoassay. Lung tissue GRP, CGRP, and PYY levels appeared to decrease gradually with time, perhaps as a result of the positive pressure ventilation procedure. GRP and CGRP levels decreased less among monkey infants ventilated with oxygen, thus they were significantly higher at 24 hours than in air ventilated controls. VIP levels were significantly lower among tests compared to controls at that time. Blood peptide levels did not change with oxygen treatment. These results suggest that tissue concentrations of certain pulmonary regulatory peptides can become altered by ventilation with greater than 95% oxygen. A blood borne peptide marker was not identified.     

Distribution and morphology of sensory and autonomic fibres in the subendocardial plexus of the rat heart

Cardiac reflexes originating from sensory receptors in the heart ensure blood supply to vital tissues and organs in the face of constantly changing demands. Atrial volume receptors are mechanically sensitive vagal afferents which relay to the medulla and hypothalamus, affecting vasopressin release and renal sympathetic activity. To date, two anatomically distinct sensory endings have been identified which may subserve cardiac mechanosensation: end-nets and flower-spray endings. To map the distribution of atrial receptors in the subendocardial space, we have double-labelled rat right atrial whole mounts for neurofilament heavy chain (NFH) and synaptic vesicle protein 2 (SV2) and generated high-resolution maps of the rat subendocardial neural plexus at the cavo-atrial region. In order to elucidate the nature of these fibres, double labelling with synaptophysin (SYN) and either NFH, calcitonin gene-related peptide (CGRP), choline acetyltransferase (ChAT) or tyrosine hydroxylase (TH) was performed. The findings show that subendocardial nerve nets are denser at the superior cavo-atrial junction than the mid-atrial region. Adluminal plexuses had the finest diameters and stained positively for synaptic vesicles (SV2 and SYN), CGRP and TH. These plexuses may represent sympathetic post-ganglionic fibres and/or sensory afferents. The latter are candidate substrates for type B volume receptors which are excited by stretch during atrial filling. Deeper nerve fibres appeared coarser and may be cholinergic (positive staining for ChAT). Flower-spray endings were never observed using immunohistochemistry but were delineated clearly with the intravital stain methylene blue. We suggest that differing nerve fibre structures form the basis by which atrial deformation and hence atrial filling is reflected to the brain.     

高血压患者硝苯地平治疗前后血浆内皮素和降钙素基因相关肽的变化

目的观察硝苯地平降压治疗对血浆内皮素（ＥＴ）和降钙素基因相关肽（ＣＧＲＰ）水平的影响。方法３１例原发性高血压（ＥＨ）患者口服硝苯地平控释片４０ｍｇ／ｄ×１４，用放免法直接测定治疗前后的血浆ＥＴ和ＣＧＲＰ水平。结果ＥＨ患者血浆ＥＴ水平明显高于对照组（８５．６±２１．０ｖｓ４２．１±２０．３ｐｇ／ｍｌ，Ｐ＜０．００１）；ＣＧＲＰ水平明显低于对照组（２３．０±８．１ｖｓ５５．４±１７．８ｐｇ／ｍｌ，Ｐ＜０．００１）。舒张压与ＥＴ水平呈正相关（ｒ＝０．５３０２，Ｐ＜０．００５），ＥＴ与ＣＧＲＰ呈弱的负相关（ｒ＝０．３７０７，Ｐ＜０．００５）。治疗后，血压和ＥＴ水平明显下降（Ｐ均＜０．００１），ＣＧＲＰ水平显著增高（Ｐ＜０．００１）。结论硝苯地平是一种有效的降压药，它可通过调节ＥＨ时多种血管活性多肽之间的平衡关系，对器官保护具有重要作用