Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience

When a high titre inhibitor develops in a patient with haemophilia, attempts are made to eradicate it through immune tolerance induction therapy (ITI) involving the frequent and regular administration of factor, usually for months to years. ITI is successful in only two thirds of patients prompting investigators to explore alternate regimens to use in haemophiliacs failing conventional ITI. Rituximab is an anti-CD20 monoclonal antibody, which has shown promise in the treatment of B-cell-mediated disorders. We developed a protocol for the use of rituximab in haemophilia A (HA) patients failing conventional ITI or in those haemophiliacs where the likelihood of success of conventional ITI is poor. Patients receive 375 mg m(-2) of intravenous rituximab weekly for 4 weeks followed by monthly (up to 5 months) until inhibitor disappearance and establishment of normal FVIII pharmacokinetics (recovery and half-life). Patients are concurrently placed on recombinant FVIII (100 U kg(-1) day(-1)). We have placed five haemophiliacs (four children with severe HA, and one adult with mild HA) on this protocol. In three patients (two with severe HA and one with mild HA) inhibitors disappeared although in neither severe haemophiliac did FVIII pharmacokinetics completely normalize. The fourth patient had a significant drop in inhibitor titres although not a complete disappearance of the inhibitor. All four of these patients ceased bleeding following rituximab. The fifth patient had no response to rituximab. This non-responding patient was not placed on concurrent FVIII. Our five cases suggest that rituximab may hold promise in the eradication of inhibitors. Prospective randomized studies are required to determine the value of this agent in inhibitor management.     

Central haemodynamics in acute myocardial infarction in relation to mortality and peak enzyme activity

The relation of central haemodynamic changes to subsequent mortalityand peak enzyme activity was investigated in 190 patients withacute myocardial infarction. The mean delay time from onsetof symptoms to the haemodynamic study was 7.2 hours. Major exclusioncriteria were heart rate < 65beats min^–1, systolicblood pressure < 105 mmHg and lung rales to a distance of> 10 cm above the lung bases. Nine patients (4.7%) died within15 days and 16 patients (8.4%) within 90 days after the infarction.Compared to survivors, non-survivors were characterized by baselinedepression of cardiac index, stroke volume index and left ventricularstroke work index, while pulmonary capillary wedge pressureand peripheral resistance were increased. However, a wide overlapbetween survivors and non-survivors makes the predictive valuelow in the individual patient. Peak serum aspartate aminotransferase (S-ASAT) activity wasweakly related to baseline pulmonary capillary wedge pressure(r = 0.28; P< 0.001) and stroke volume index (r = –0.22;P7lt;0.01). The correlation to pulmonary capillary wedge pressurewas only found in anterior (r = 0.34) infarcts. Peak serum lactatedehydrogenase (LD¹) was not correlated with baseline haemodynamics.     

The transition from injecting to smoking heroin in three Spanish cities

Aims. To measure the current prevalence of different routes of heroin administration among users and to describe the most frequent patterns in the evolution of the main route from the time of first use to the present and their implications for the control of the HIV epidemic. Design. Cross-sectional study. Face-to-face interviews using a structured questionnaire. Setting and participants. Nine hundred and nine regular heroin users from Madrid, Barcelona and Seville (about 300 per city), half of them recruited in treatment centres and the other half out of treatment. Measurements. Socio-demographic characteristics, current and historical behaviours related to route of administration. Findings. Before 1980 injection was the first main route of heroin administration for most users in Barcelona and Madrid; in Seville smoking already predominated, although 40% of users began by injecting. Sniffing subsequently became predominant in Barcelona, while smoking became the predominant first route in Madrid and Seville (smoking has been the only first route in Seville since 1991). The prevalence of injection as the main route of administration during the last 30 days was 77.3% in Barcelona, 24.3% in Madrid and 23.9% in Seville; smoking predominated in the latter two cities. The factors most strongly associated with injection as the preferred route were city of recruitment and having a partner who injected. Some 73% of those who stopped injecting in their last change of route stated that the results of their HIV test or fear of becoming infected had been important in making this decision. Conclusions. The change from injecting to smoking will greatly facilitate the control of HIV infection in Spain. However, the main causal factor does not appear to be the perception of HIV risk, but rather other, ecological factors (cultural or market-related). The absence of these factors in some areas may impede the spread of smoking.     

Obliterative portal venopathy: A comparative study of 184 cases of extrahepatic portal obstruction and 469 cases of idiopathic portal hypertension

Abstract A total of 184 cases of extrahepatic portal obstruction (EHPO), mostly demonstrated by intraoperative portography and studied at 17 institutes during the period 1957–1983, were compared with 469 cases of idiopathic portal hypertension (IPH) similarly studied. Of the cases of EHPO, there were 101 males and 83 females; 93 were under 20 years of age and the average age was 25.9 years (i.e. much younger than that of IPH cases). There were two age peaks, one before age 19 years and the other at age 40–49 years. One out of three adult cases had a history of abdominal surgery, but otherwise the aetiologic factor was difficult to elicit. Bleeding was the initial symptom in the majority, and splenectomy and haematological findings of hypersplenism were less pronounced compared with IPH. Liver function tests were almost always normal. The liver appeared normal macroscopically in 69% and histologically in 35%. The changes seen in the remainder were similar to those in IPH; they were less frequent in young patients than in cases above age 20 years. Compared with IPH, the wedged hepatic venous pressure in patients with EHPO was lower and the gradient from the portal venous pressure was greater. It is concluded that extrahepatic portal obstruction is less common compared with IPH in Japan, and that there are cases particularly among adults that present clinicopathological features very similar to those of IPH. It is unclear at present whether these two disorders represent two different disease entities, or whether they represent one disorder with differences in the site of involvement along the portal vein system.     

Effects of amlodipine on transient myocardial ischaemia in patients with a severe coronary condition treated with a beta-blocker

The purpose of this trial was to study the additional anti-ischaemiceffects of amlodipine in coronary patients with ambulant ischaemiadespite beta-blocker therapy. Beta-blockers are the most effectivedrug therapy for reducing the frequency and duration of ambulatoryischaemic episodes. However, the therapeutic advantage of combinedcalcium antagonist-beta-blocker treatment remains questionable. Three hundred and thirteen patients with documented coronaryartery disease, a positive exercise test within 6 months beforeentry and background beta-blocker therapy, were screened. Inclusioncriteria (4 episodes of transient ST segment depression of 1.0 mm and/or 20 min of ischaemia) were demonstrated in a 48h ECG during the placebo run-in period in 84 (25%) of the patients.Eighty-nine percent of the ischaemic episodes were silent. Theeligible patients were then randomized in a 2-week, double-blind,parallel group study comparing placebo to amlodipune 10 mg dailyadded to the beta-blocker. The anti-ischaemic efficacy of thecombination therapy was assessed by 48 h ECG monitoring andexercise tests. Compared to placebo, amlodipine did not significantly reduceeither the frequency (3.7±4.3 vs 4±4.8 episodesin the amlodipune group) or the duration of ambulatory ischaemia(mean duration: 43.9±57.1 vs 39.6±65.7 min, totalduration 3.1±6.7 vs 2.8±6.1 h). Exercise-inducedST segment depression tended to decrease with amlodipine (58%vs 73% in the placebo group) and the ischaemia-free workloadcapacity was increased (+1.7 stage vs 0.7 stage in the placebogroup, P=0.08). These results suggest that 2 weeks treatment with amlodipinemay not provide any additional anti-ischaemic benefit in patientswith ambulant ischaemia resistant to a beta-blocker therapy.     

Safety of flecainide versus propafenone for the long-term management of symptomatic paroxysmal supraventricular tachyarrhythmias: Report from the Flecainide and Propafenone Italian Study (FAPIS) group

In order to compare the long-term safety of flecainide and propafenone,an open label, randomized, parallel group study was performedin 335 patients with paroxysmal atrial fibrillation (n=200)or paroxysmal supra ventricular tachycardia (n=135), and nohistory of heart disease. Patients were treated with an initialdaily dose of flecainide 100 mg (n=72) or propafenone 450 mg(n=63) for paroxysmal supraventricular tachycardia and flecainide200 mg (n=97) or propafenone 450 mg (n=103) for paroxysmal atrialfibrillation. Dose escalations were permitted after 2 attacks,up to a maximum of flecainide 300 mg or propafenone 900 mg.day^–1. Follow-up duration was 12 months, or when patientsstopped the treatment as a result of inadequate efficacy oradverse experiences. Twelve patients on flecainide reported 16 cardiac adverse experiences,of whom six discontinued the treatment. Seven propafenone patientshad eight cardiac adverse experiences, of whom five discontinuedthe treatment. Serious proarrhythmic events were infrequent:one case of ventricular tachycardia on propafenone; two casesof atrial fibrillation with rapid ventricular response on flecainide,associated in one patient with pulmonary oedema. An intention-to-treat analysis showed that the probability of12 months' safe and effective treatment of paroxysmal supraventriculartachycardia was 93% for flecainide and 86% for propafenone (P=0·24),whereas in paroxysmal atrial fibrillation it was 77% for flecainideand 75% for propafenone (P=0·72). In conclusion, flecainide and propafenone were safe in the long-termtreatment of patients with paroxysmal supraventricular tachyarrhythmiasand without evidence of clinically significant heart disease.