Repetitive dihydroergotamine nasal spray for treatment of refractory headaches:an open-label pilot study

ABSTRACT

Objective: To evaluate the safety and efficacy of a repetitive intranasal (IN) dihydroergotamine (DHE) burst protocol for treatment of refractory headaches.

Research design and methods: Patients with refractory headaches were enrolled in a prospective, open-label, pilot study. Patients were instructed to self-administer IN DHE every 8 hours for 3 days; each IN DHE dose consisted of one 0.5-mg spray in each nostril that was repeated 15 minutes later, for a total of 2.0?mg DHE per dose. Follow-up visits were scheduled approximately 3 weeks later.

Main outcome measures: Efficacy and safety measurements were collected during patient interviews. Primary efficacy measures were the change in headache frequency, duration, and severity (rated from 0 [none] to 5 [extremely severe]) between the initial and follow-up visits. Safety was assessed at the follow-up visits through the occurrence of adverse events (AEs).

Results: Twenty-six patients were enrolled in the study. Follow-up visits were completed by 24 patients whose mean headache frequency at study entry was 6.6 d/wk. The IN DHE burst protocol was associated with significant mean decreases in headache frequency (2.6 d/wk, p < 0.001), duration (5.8 hours, p = 0.03), and severity (1.2 units, p < 0.001) between study entry and the follow-up visit. One patient discontinued IN DHE use early because of an AE (nasal stuffiness); two additional patients each reported one AE (fatigue and increased headache) that was attributed to IN DHE.

Conclusions: The results of this pilot study suggest that the IN DHE burst protocol may be an effective and safe treatment for refractory headaches; interpretation of these results is limited by the open-label, uncontrolled design and the small number of patients. The development of a doubleblind, placebo-controlled study to further evaluate this treatment regimen is warranted.     

鼻炎分类和诊断及鼻腔用药方案的专家共识

目的本文基于临床经验和循证医学证据制定的鼻炎（萎缩性鼻炎除外）分类和诊疗的专家共识,其中在治疗方面重点关注了鼻腔局部用药的临床应用,旨在进一步规范鼻炎尤其是慢性鼻炎的诊疗,明确鼻腔局部用药如鼻用糖皮质激素、鼻用抗组胺药和鼻腔盐水盥洗等在鼻炎治疗中的临床地位及注意事项,以便指导临床医师进行合理用药,提高鼻炎的疗效和患者的满意度。     

鼻内针刺对变应性鼻炎兔神经源性炎性反应的影响

目的:观察鼻内针刺对变应性鼻炎(AR)新西兰兔鼻黏膜P物质(SP)、血管活性肠肽(VIP)、神经肽Y(NPY)蛋白表达及血清免疫球蛋白E(IgE)、白细胞介素4(IL-4)、干扰素-γ(IFN-γ)含量的影响,探讨鼻内针刺治疗AR的机制。方法:新西兰兔采用随机数字表法随机分为正常组、模型组、非经非穴组和鼻内针刺组,每组8只。采用卵蛋白腹腔注射及鼻黏膜刺激法建立AR新西兰兔模型。鼻内针刺组针刺两侧鼻腔"内迎香"穴(下鼻甲前端附着区距鼻阈1 cm处),非经非穴组浅刺面部两颊外缘处(非穴位浅刺),两组均留针20 min,隔日治疗1次,共7次。干预前后观察各组新西兰兔行为学变化,采用免疫组织化学法检测鼻黏膜SP、VIP、NPY的表达,采用酶联免疫吸附法检测血清IgE、IL-4、IFN-γ含量。结果:治疗前后,模型组症状积分均明显高于正常组(P<0.01);治疗后,与模型组及非经非穴组比较,鼻内针刺组症状积分明显下降(P<0.05)。模型组新西兰兔鼻黏膜SP、VIP表达明显高于正常组(P<0.01),NPY的表达明显低于正常组(P<0.05);鼻内针刺组鼻黏膜SP、VIP表达明显低于模型组及非经非穴组(P<0.01),NPY的表达明显高于模型组及非经非穴组(P<0.05)。模型组血清IgE、IL-4含量明显高于正常组(P<0.05),IFN-γ含量明显低于正常组(P<0.01);鼻内针刺组血清IgE、IL-4含量明显低于模型组及非经非穴组(P<0.05),IFN-γ含量显著高于模型组及非经非穴组(P<0.01)。鼻黏膜SP、VIP积分吸光度值与血清IgE、IL-4含量呈正相关(P<0.05),与血清IFN-γ含量呈负相关(P<0.05)。结论:鼻内针刺治疗可明显降低鼻黏膜感觉神经及副交感神经兴奋性,提升交感神经兴奋性,并以相应神经肽为介质,通过神经免疫系统调控免疫应答,进而改善神经源性炎性反应,缓解鼻部症状。     

Neuroprotective effects of melatonin against neurotoxicity induced by intranasal sodium dimethyldithiocarbamate administration in mice

Exposure to fungicide ziram (zinc dimethyldithiocarbamate) has been associated with increased incidence of Parkinson’s disease (PD). We recently demonstrated that the intranasal (i.n.) administration of sodium dimethyldithiocarbamate (NaDMDC, a more soluble salt than ziram) induces PD-like behavioral and neurochemical alterations in mice. We now investigated the putative neuroprotective effects of melatonin on behavioral dificits and neurochemical alterations induced by i.n. NaDMDC. Melatonin treatment (3, 10 or 30 mg/kg, i.p.) was given 1 h before NaDMDC administration (1 mg/nostril) during 4 consecutive days and we evaluated early (up to 7 days) and late (up to 35 days) NaDMDC-induced behavioral and neurochemical alterations. Melatonin treatment protected against early motor and general neurological impairments observed in the open field and neurological score of severity, respectively, and late deficits in rotarod test. Melatonin prevented the NaDMDC-induced alterations in the striatal tyrosine hydroxylase immunocontent. Melatonin also protected against increased levels of oxidative stress markers (4-hydroxynonenal and 3-nitrotyrosine) in the striatum, as well as the NaDMDC-induced increase of 4-hydroxynonenal and TNF, markers of oxidative stress and inflammation, respectively, in the olfactory bulb. These results further detail the mechanisms underlying NaDMDC toxicity and demonstrate the neuroprotective effects of melatonin against the neuronal damage induced by NaDMDC.     

Tolerance of Fentanyl Pectin Nasal Spray for Procedural Pain in Geriatric Patients

ObjectivesWe aimed to assess the tolerance of fentanyl pectin nasal spray (FPNS) when used to treat procedural pain caused by wound dressing or physiotherapy in patients older than 75 years with or without opioid background treatment.DesignThis is a prospective monocentric, noncontrolled, nonrandomized study conducted from December 2014 to October 2017 in 2 geriatric wards (rehabilitation and acute medicine).Setting and ParticipantsFifty-seven patients were included and 314 procedures were monitored.MethodsFor each patient, 6 procedures were monitored: the first 2 without specific treatment, then fentanyl was started at 100 μg with a titration over a few procedures up to 800 μg in non–opioid-naïve patients and 400 μg in opioid-naïve. Sedation and respiratory scale were monitored during the procedures. All adverse drug events occurring from inclusion to 5 days after the intervention were collected and their imputability was assessed separately by 2 pharmacovigilance experts.ResultsOverall, 14.4% of the sessions with FPNS administration resulted in adverse drug events. Main adverse drug events were nausea and vomiting, somnolence, and confusion. Most of them were of mild to moderate severity. Four severe adverse events were due to accidental overdoses. No unexpected adverse event occurred. Tolerance was similar for opioid-naïve and non–opioid-naïve patients (P value = .93).Conclusion and implicationsFPNS was overall well tolerated in geriatric patients. Given its interesting pharmacokinetics, fentanyl is a promising lead for procedural pain treatment in geriatric patients, even those who are opioid naïve.     

Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

Allopregnanolone, a positive modulator of GABA_A receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED₅₀, 5.6 mg/kg), picrotoxin (ED₅₀, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a T_max of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (C_max, 16,000 ng/mg) whereas much lower levels (C_max, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00985-5.     

Pharmacodynamics of acute intranasal administration of verapamil: comparison with i.v. and oral administration

The present study was conducted in order to examine the intranasal administration of verapamil and compare this route to oral and intravenous administration in a 3 way crossover protocol in five dogs. Unanesthetized, adult mongrel dogs were given verapamil intravenously (0.5 mg/kg), orally (2.5 mg/kg) and intranasally (0.75 mg/kg) with at least a 3-4 day washout period between each administration. Blood samples were collected over a 10 hour period and analyzed for verapamil using HPLC with fluorescence detection. A lead II ECG was monitored to determine the effects of verapamil on heart rate and P-R interval. Following intravenous administration, verapamil was distributed according to a two compartment model. Bioavailability (corrected for dose and elimination rate constant) following intranasal administration (36% +/- 7%) was approximately 3 fold that after oral administration (13% +/- 3%). Absorption from the nasal cavity appeared instantaneous compared to an absorption half-life of 50 +/- 6 min after oral administration. All three routes of administration resulted in significant increases in heart rate and increases in the P-R interval. Maximal P-R interval prolongation occurred after peak plasma concentrations of verapamil. The results of this study suggest that the intranasal route is a viable alternative route of administration for verapamil.     

Quantitative analysis of the olfactory pathway for drug delivery to the brain

Following intranasal administration to rats, wheat germ agglutinin-horseradish peroxidase (WGA-HRP) concentrated in the olfactory nerve and glomerular layers of the olfactory bulb resulting in a mean olfactory bulb concentration of 140 nM. A negligible amount of label was detected in the olfactory bulb following intravenous administration of WGA-HRP or intranasal administration of unconjugated HRP. This is the first quantitative assessment of intraneuronal transport of a protein into the brain using the olfactory route.     

Salmon calcitonin (Miacalcic) nasal spray in prevention and treatment of osteoporosis

Calcitonin (CT) constitutes one of the major choices for the pharmacologic treatment of postmenopausal and senile osteoporosis. In postmenopausal osteoporosis, CT, analogous to estrogens, determines increase of bone mass, improvement of intestinal calcium absorption and a positivization of calcium balance. Patients treated with CT can also benefit from the analgesic effect of the hormone. Unlike estrogens, these beneficial effects of CT occur with minimal risk and require no routine gynecological monitoring. In addition, CT is completely devoid of toxicity. The only limitations to the use of CT are linked to the frequent parenteral injections and the occurrence of side effects. These limitations can now be overcome by the availability of the new nasal spray preparation, which has been developed for synthetic salmon calcitonin (sCT). The introduction of this new form increases the patients' compliance, and the different pharmacokinetic curtails the side effects, compared to the parenteral administration. At present, one-year controlled studies have been reported, showing a beneficial effect of sCT on bone mass in patients with established osteoporosis. Also, shorter studies demonstrate the analgesic activity of sCT treatment in patients with vertebral crush fractures and bone pain. The improvement in the patients' compliance and the reduction of side effects allow this new CT preparation to be used in the prevention of post-menopausal osteoporosis.