Breakthrough Attacks Research Articles

Are these patients indeed resistant to treatment with C1 inhibitor concentrate?

Funding sources: none. Conflicts of interest: none declared. Madam, Bouillet et al.1 report two remarkable cases of patients with type I hereditary angio‐oedema (HAE) who developed ‘resistance against C1 inhibitor concentrate’. In our view, however, the authors failed to substantiate the statement made in the title of their article (‘… patients with hereditary angio‐oedema type I resistant to treatment with C1 inhibitor concentrate’). The severity of HAE fluctuates during the lifetime of afflicted patients, regardless of permanent C1 inhibitor deficiency. External factors are known potential inducers of oedematous attacks, the frequency of which may increase in their presence. However, variations of attack frequency can occur both in untreated patients and in those on a stable prophylactic regimen. This was the case in patient 1, who began to experience breakthrough attacks despite unchanged treatment, and whose attacks could not be eliminated even by increasing the dose of C1 inhibitor concentrate to the standard level recommended for prophylaxis (see the U.S. Food and Drug Administration package insert of Cinryze®2). The authors mention breakthrough attacks, but do not provide any information on the frequency and duration of these episodes.

Case report of treatment with Icatibant for recurrent throat swelling due to hereditary angioedema

Department of Medicine, Division of Clinical Immunology and Allergy, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5 We report a 64 year-old woman with longstanding hereditary angioedema who previously required a tracheotomy. In September 2005, while receiving prophylactic Danazol she noticed a left sided swelling involving her throat and uvula that was of moderate intensity by 1110h. She came to hospital and received icatibant 30 mg sc at 1330h when the swelling was 1 cm in size. One hour later the swelling was 4 mm in size. After 2 hours the swelling was gone and did not recur. Because of increased frequency of angioedema, after December 2008 she started taking C1 esterase inhibitor 2000 PU once weekly, and Danazol 400 mg daily plus additional C1 inhibitor infusions when symptoms were uncontrolled. She received icatibant in August 2009 for throat swelling. Her symptoms subsided and admission wasn’t required. In November 2009, she was admitted for a bowel obstruction due to angioedema. She received a single dose of icatibant, but did not note any benefit. Treatment with icatibant was not repeated. With conservative treatment and additional C1 esterase inhibitor, her bowel obstruction gradually resolved over 3 days. Her C4 was undetectable (<0.02 g/L) and C1 esterase inhibitor was within the normal range (0.22 g/L normal 0.21-0.39 g/L). We present a patient with hereditary angioedema whose throat angioedema responded to icatibant but a single dose of icatibant did not have significant effect on bowel angioedema. Physicians should consider icatibant for breakthrough attacks not prevented by prophylactic therapy.

Oral Zolmitriptan in the Short-Term Prevention of Menstrual Migraine

To evaluate the efficacy and tolerability of oral zolmitriptan as a short-term preventative therapy for menstrual migraine. This was a randomized, double-blind, parallel group, placebo-controlled, multicentre, two-phase study. The results of the second phase are reported here (the first phase evaluated zolmitriptan in the acute treatment of menstrual migraine and is reported elsewhere). Women who successfully completed phase I (with either a positive or negative outcome, and who still fulfilled the inclusion criteria) were randomized to zolmitriptan 2.5 mg oral tablet three times daily, zolmitriptan 2.5 mg twice daily or placebo three times daily. Patients were treated for three consecutive menstrual cycles, starting 2 days prior to the expected onset of menses, for 7 days in total. Two hundred and fifty-three patients completed phase I and were eligible for phase II. The intention-to-treat population comprised 244 patients (zolmitriptan three times daily [n = 83]; zolmitriptan twice daily [n = 80]; placebo [n = 81]). Both zolmitriptan regimens demonstrated superior efficacy versus placebo, as measured by the proportion of patients with a >or=50% reduction in the frequency of menstrual migraine attacks (zolmitriptan three times daily [58.6%], p = 0.0007 vs placebo; zolmitriptan twice daily [54.7%], p = 0.002 vs placebo; placebo three times daily [37.8%]). The mean frequency of breakthrough migraine attacks per menstrual cycle was reduced accordingly. Fewer breakthrough attacks were treated with escape medication in the zolmitriptan three times daily (61.6% of attacks; p = 0.0004 vs placebo) and twice daily (60.7%; p = 0.0055 vs placebo) treatment groups than in the placebo group (74.4%). Short-term preventative therapy with zolmitriptan was well tolerated. Zolmitriptan 2.5 mg oral tablet is effective and well tolerated as a short-term preventative therapy for menstrual migraine attacks.

Open‐Label, Long‐Term Tolerability of Naratriptan for Short‐Term Prevention of Menstrually Related Migraine

Although naratriptan is not approved for prophylactic use in migraine, naratriptan has been shown to be significantly more effective than placebo for short-term prevention of menstrually related migraine (MRM). The tolerability of naratriptan administered intermittently for prophylaxis for MRM over the long term has not been assessed. To assess the tolerability of naratriptan 1 mg given twice daily for 6 days per month, administered for up to 1 year for short-term prevention of MRM in an open-label study. Patients were eligible for the study if they were between 18 and 65 years of age and had at least a 1-year history of migraine, with or without aura, as defined by 1988 International Headache Society criteria; reported a history of MRM; and had at least 1 MRM attack during their last menstrual cycle. MRM was defined as any migraine beginning during the perimenstrual period (PMP). By definition, the PMP consisted of Days -2, -1, 1, 2, 3, and 4, with Day 1 being the first day of menstrual flow. During each menstrual cycle occurring over a 1-year period, patients began short-term treatment with naratriptan 1 mg twice daily (BID) 3 days before the expected onset of MRM and treated for a total of 6 days. Naratriptan 2.5 mg could be taken for breakthrough MRM attacks. Tolerability and safety measures included adverse events, standard clinical laboratory tests, electrocardiograms (ECGs), and vital signs. The secondary endpoints were the percentage of PMPs without MRM; headache disability as measured by the Headache Impact Test (HIT), and psychological health as measured by the Beck Depression Inventory version 2 (BDI-II). The number of patients who took at least 1 dose of study medication (safety population) was 457, and the numbers of patients completing 6 months and 12 months of treatment were 318 and 131, respectively. Note that 171 (37%) patients were asked to leave the study once target enrollment numbers were met. The only adverse event occurring at an incidence of more than 2% during the 6-day treatment periods when naratriptan 1 mg BID was taken with or without an additional 2.5-mg dose for breakthrough attacks was ear, nose, throat infection (3%). No specific adverse event considered at least possibly to be related to study medication occurred in more than 2% of patients. No serious drug-related adverse events were reported. Furthermore, no patient experienced clinically relevant drug-related changes in 12-lead ECGs, vital signs, or clinical laboratory tests. Patients in both the 6- and 12-month populations did not experience an MRM in approximately 50% of treated PMPs. Health outcomes results suggested that naratriptan reduced headache impact when used for up to 12 months for the short-term prevention of MRM. Naratriptan 1 mg BID, with the optional use of an additional 2.5-mg dose for breakthrough attacks, was well tolerated when used for 6 continuous days per month for up to 1 year for short-term prevention of MRM.

Early predictors of medical intractability in childhood epilepsy

The goal of this study is identify early predictors of intractability in childhood epilepsy. A cohort of epileptic children living in the northwest sector of Hong Kong was prospectively identified and monitored. Treatment effect was analyzed at the last follow-up before July 1, 2000. Cases were patients who had an average of at least one unprovoked seizure per month during an observational period of at least 2 years. Controls were children having achieved at least 2 seizure-free years. Strong univariate association was observed between intractability and the following factors: high initial seizure frequency, remote symptomatic etiology, infantile spasms and mixed seizure types, abnormal neurologic status, history of status epilepticus, neonatal seizures, and early breakthrough attacks after treatment initiation. Independent predictors of intractability with multiple regression were abnormal neurodevelopmental status, symptomatic etiology, and more than three seizures in the second 6 months after treatment. Our study suggested that risk of developing intractable epilepsy might be predicted, to some extent, at the early course of illness in children with abnormal neurologic status and lack of early response to treatment.

Methysergide.

Methysergide is a semisynthetic ergot alkaloid ergometrine derivative, introduced in pharmacotherapy for migraine prophylaxis as a specific serotonin (5HT) receptor antagonist. Methysergide is not just a 5HT2 antagonist, it is also a 5HT1 agonist. Open and controlled studies attest to methysergide's efficacy. It may be more effective in resistant cases with a high attack frequency and may act synergistically with ergotamine and dihydroergotamine (DHE) for breakthrough attacks. Contraindications include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, fibrotic disorders, lung diseases, collagen disease, liver or renal function impairment, valvular heart disease, debilitation, or serious infection. Methysergide can induce retroperitoneal fibrosis and pleural and heart valve fibrosis with an estimated incidence of 1 in 5,000 treated patients. Therefore, it should be reserved for severe cases in which other migraine preventive drugs are not effective.

A Review of Current Treatments for Migraine

Acute drug therapy is the mainstay of treatment for migraine sufferers, with prophylaxis reserved for those with frequent or severe attacks. The majority of treatments have been in use for many years, although their value is often poorly documented due to a lack of well-controlled trials undertaken with defined diagnostic criteria and study end-points. Analgesics with anti-emetics, nonsteroidal anti-inflammatory drugs and ergot derivatives are used for acute treatment. Recently, the selective 5-HT1 receptor agonist sumatriptan has become available and been shown to have significant benefits over traditional therapies for the acute treatment of migraine. Beta-blockers, flunarizine and 5-HT2 antagonists have been used for prophylaxis, and although many patients report a reduction in attack frequency, breakthrough attacks still occur.

Salmeterol: an inhaled beta 2-agonist with prolonged duration of action.

Salmeterol (Serevent) is an inhaled beta 2-receptor agonist with more than twelve hours' effect duration compared with 4-6 hours for the more short-acting substances bitolterol, fenoterol, salbutamol, and terbutaline. Salmeterol has been studied in several large-scale double-blind multicenter studies with up to one year's duration. More than 6,000 asthmatics have been treated with salmeterol during these controlled studies. All studies show salmeterol to have a significantly better and well-maintained bronchodilating effect with better asthma control, fewer asthma exacerbations, and a decreased need for rescue albuterol inhalations used on demand compared to the treatments in the control groups (200-400 micrograms albuterol q.i.d., inhaled albuterol given only p.r.n., terbutaline given regularly, or individually titrated slow-release theophylline). Salmeterol should be given b.i.d. and in combination with inhaled corticosteroids. Salmeterol seems especially effective in patients with nocturnal symptoms, exercise induced asthma, and in patients sensitive to inhaled irritants such as cold air. The patients should always have short-acting inhaled beta 2-agonists available for break-through attacks. Inhaled salmeterol in combination with inhaled steroids seems to give the best maintenance asthma control available by inhalation today.

The use of in-vitro sensitivity testing to predict clinical response of recurrent herpes simplex to suppressive oral acyclovir.

Twenty-six pre-treatment isolates of herpes simplex virus from 20 immunocompetent patients with frequently recurring mucocutaneous herpes were tested for in-vitro sensitivity by a plaque reduction assay. When correlated with the occurrence of breakthrough attacks during subsequent courses of suppressive treatment with oral acyclovir the mean ID50, ID90 and ID99 were all found to be significantly higher for isolates associated with breakthroughs. However, cut-off values could only be set for the ID90 and ID99 values. An ID99 less than 0.75 mg/l was found in 17/21 (81%) of isolates not associated with breakthrough attacks, but none of five isolates associated with breakthroughs. The corresponding findings for an ID90 less than 0.5 mg/l were 17/21 (81%) without breakthroughs and 1/5 with breakthroughs. It is suggested that the ID90 and ID99 are better predictors of the clinical response to suppressive oral acyclovir than is the ID50. Possibly this is because they better reflect the presence of viral strains with reduced sensitivity which may be responsible for breakthrough attacks.