Guideline on the use of onabotulinumtoxinA in chronic migraine: a consensus statement from the European Headache Federation

OnabotulinumtoxinA is being increasingly used in the management of chronic migraine (CM). Treatment with onabotulinumtoxinA poses challenges compared with traditional therapy with orally administered preventatives. The European Headache Federation identified an expert group that was asked to develop the present guideline to provide recommendations for the use of onabotulinumtoxinA in CM. The expert group recommend onabotulinumtoxinA as an effective and well-tolerated treatment of CM. Patients should preferably have tried two to three other migraine prophylactics before start of onabotulinumtoxinA. Patients with medication overuse should be withdrawn from the overused medication before initiation of onabotulinumtoxinA if feasible, if not onabotulinumtoxinA can be initiated from the start or before withdrawal. OnabotulinumtoxinA should be administered according to the PREEMPT injection protocol, i.e. injecting 155 U–195 U to 31–39 sites every 12-weeks. We recommend that patients are defined as non-responders, if they have less than 30% reduction in headache days per month during treatment with onabotulinumtoxinA. However other factors such as headache intensity, disability and patient preferences should also be considered when evaluating response. Treatment should be stopped, if the patient does not respond to the first two to three treatment cycles. Response to continued treatment with onabotulinumtoxinA should be evaluated by comparing the 4 weeks before with the 4 weeks after each treatment cycle. It is recommended that treatment is stopped in patients with a reduction to less than 10 headache days per month for 3 months and that patients are re-evaluated 4–5 months after stopping onabotulinumtoxinA to make sure that the patient has not returned to CM. Questions regarding efficacy and tolerability of onabotulinumtoxinA could be answered on the basis of scientific evidence. The other recommendations were mainly based on expert opinion. Future research on the treatment of CM with onabotulinumtoxinA may further improve the management of this highly disabling disorder.     

Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease

BACKGROUND AND AIMS: Cardiac dysfunction may be present in patients with cirrhosis. This study was undertaken to relate plasma concentrations of cardiac peptides reflecting early ventricular dysfunction (pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP)) to markers of severity of liver disease, cardiac dysfunction, and hyperdynamic circulation in patients with cirrhosis. PATIENTS AND METHODS: Circulating levels of proBNP and BNP were determined in 51 cirrhotic patients during a haemodynamic investigation. RESULTS: Plasma proBNP and BNP were significantly increased in cirrhotic patients (19 and 12 pmol/l, respectively) compared with age matched controls (14 and 6 pmol/l; p<0.02) and healthy subjects (<15 and <5.3 pmol/l; p<0.002). Circulating proBNP and BNP were closely correlated (r = 0.89, p<0.001), and the concentration ratio proBNP/BNP was similar to that of control subjects (1.8 v 2.3; NS). Circulating proBNP and BNP were related to severity of liver disease (Child score, serum albumin, coagulation factors 2, 7, and 10, and hepatic venous pressure gradient) and to markers of cardiac dysfunction (QT interval, heart rate, plasma volume) but not to indicators of the hyperdynamic circulation. Moreover, in multiple regression analysis, proBNP and BNP were also related to arterial carbon dioxide and oxygen tensions. The rate of hepatic disposal of proBNP and BNP was not significantly different in cirrhotic patients and controls. CONCLUSION: Elevated circulating levels of proBNP and BNP in patients with cirrhosis most likely reflects increased cardiac ventricular generation of these peptides and thus indicates the presence of cardiac dysfunction, rather than being caused by the hyperdynamic circulatory changes found in these patients.     

Hemolytic Disease of the Newborn Apparently Caused by Anti-Lua

Report of the first example of pure anti-Lu^a associated with hemolytic disease of the newborn. Of special interest is the fact that this serum demonstrated a marked prozone reaction in saline, papain and indirect Coombs titrations, and is the first anti-Lu^a serum to react well by the indirect Coombs technic.     

Efficacy and safety of terlipressin in cirrhotic patients with variceal bleeding or hepatorenal syndrome

Terlipressin is an analog of the natural hormone arginine-vasopressin. It is used in the treatment of patients with cirrhosis and bleeding esophageal varices (BEV) and in patients with hepatorenal syndrome (HRS): two of the most dramatic and feared complications of cirrhosis. Terlipressin exerts its main pharmacological effect through stimulation of vasopressin-1 receptors. These receptors are located in vascular smooth muscle and mediate vasoconstriction. In patients with cirrhosis and portal hypertension, treatment with terlipressin increases mean arterial pressure and decreases portal flow and pressure within minutes of administration. Furthermore, in patients with ascites terlipressin improves glomerular filtration and excretion of sodium. Terlipressin decreases failure of initial hemostasis by 34%, decreases mortality by 34%, and is considered a first-line treatment for BEV, when available. Terlipressin in combination with albumin reverses type 1 HRS in 33%–60% of cases and is the only treatment with proven efficacy in randomized trials. The safety profile is favorable when considering the clinical efficacy and the high mortality of these clinical entities. Adverse events are mostly cardiovascular and related to vasoconstriction. Mortality and withdrawal of terlipressin due to adverse events occurs in less than 1% of cases. Mild adverse events related to terlipressin treatment occur in 10%–20% of patients. The benefit, however, of terlipressin on long-term survival in HRS remains to be determined. At present, treatment with terlipressin and albumin is considered the most efficient therapy and should therefore be recommended for the treatment of type 1 HRS-1.     

A randomised controlled trial of ultrasound‐guided blockade of the saphenous nerve and the posterior branch of the obturator nerve for postoperative analgesia after day‐case knee arthroscopy

The purpose of this study was to investigate the effects of blockade of the saphenous nerve and the posterior branch of the obturator nerve in addition to a standard analgesic regimen for patients discharged the same day after knee arthroscopy. The primary outcome was knee pain on flexion during the first 24 postoperative hours, calculated as area under the curve. We allocated 60 patients to ultrasound‐guided nerve blocks with either ropivacaine or saline, 30 to each. The median (IQR [range]) pain score on knee flexion in the ropivacaine group 2.0 (1.1–3.7 [0.1–7.1]) was not statistically different to that in the saline group (3.3 (1.7–4.6 [0.3–6.8]), p = 0.06). There were no differences in pain at rest, opioid consumption or function.     

Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide

Pharmaceutical Research - The aim of this work is to investigate the roles of solute carrier family 22 member 18 (SLC22A18) in lipid metabolism and in establishing the tumor phenotype of HepG2...     

Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition

The tricyclic antidepressant amitriptyline is the only documented and most widely used prophylactic drug for chronic tension-type headache (CTTH). However, it is not fully clarified whether the serotonin (5-HT) reuptake inhibition plays a major role for the analgesic effect of amitriptyline. To explore the importance of 5-HT reuptake inhibition for mechanism of action of the analgesic effect of amitriptyline we investigated platelet 5-HT levels during preventive treatment of CTTH with amitriptyline, the selective serotonin reuptake inhibitor citalopram, and placebo. Thirty-four patients with CTTH were given preventive treatment with amitriptyline 75 mg/day, the selective 5-HT reuptake inhibitor citalopram 20 mg/day, and placebo in a 32-week, double-blind, placebo-controlled, three-way crossover trial. Blood samples were collected in the last week of each treatment period. Platelet 5-HT was used as a measure of 5-HT reuptake inhibition and determined by high performance liquid chromatography. Area under the headache curve was 308 (157-715) (median with quartiles in parentheses) with amitriptyline and significantly lower than 377 (158-1121) with citalopram (P = 0.04) and 441 (178-1408) with placebo (P = 0.002). There was no difference between citalopram and placebo (P = 0.23). Platelet 5-HT was 0.4 (0.3-0.7) x 10(-18)mol/platelet with citalopram, which was significantly lower than 1.7 (1.2-2.4) x 10(-18)mol/platelet with amitriptyline (P < 0.001), and 3.5 (2.8-4.3) x 10(-18)mol/platelet with placebo (P < 0.001). The lower platelet 5-HT during treatment with citalopram than amitriptyline indicates that 5-HT reuptake was most effectively inhibited by citalopram. In contrast, amitriptyline was most effective in reduction of headache. This suggests that the analgesic effect of amitriptyline in CTTH is not solely due to 5-HT reuptake inhibition and that other mechanisms such as norepinephrine reuptake inhibition, NMDA receptor antagonism, blockade of muscarinic receptors and ion channels should be addressed in the future research.