QT interval monitoring during clinical studies with mizolastine, a new H1 antihistamine.

BACKGROUND: Some H1 antihistamines are at risk for rare but severe dysrhythmias due to an effect on the ventricular repolarization. OBJECTIVE: To present an overview of the QT interval monitoring performed during the clinical development of mizolastine, a new selective second-generation H1 antihistamine. METHODS: The ECGs database analysis of clinical studies conducted in volunteers and patients is summarized and focused on the results of reported studies and studies specifically designed for the assessment of the effect of mizolastine on cardiac repolarization, through the QT interval measurements. Mizolastine was orally administered up to 75 mg single dose and 40 mg repeated dose in healthy volunteers (i.e. 7. 5 and 4 times the recommended dose, respectively) and at a dose of 10 or 15 mg in patients. RESULTS: In healthy volunteers, no increased incidence of QTc values >440 msec or DeltaQTc >/=40 msec were recorded compared to placebo. No dose-related increase in QTc interval was observed. The ECG parameters were not modified by the co-administration of mizolastine with digoxin, diltiazem and erythromycin, when compared to the effect of each co-administered drug alone. In patients, the mean QTc interval changes from baseline did not significantly differ from placebo. In comparative studies vs. loratadine a similar incidence of out of range values was observed with mizolastine and loratadine. CONCLUSION: ECG monitoring of volunteers and patients included in clinical studies conducted with mizolastine showed no significant effect of mizolastine on cardiac repolarization.

Sustained-release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group.

OBJECTIVES: To assess the additive benefit of combining an alpha1-blocker and a 5alpha-reductase inhibitor. METHODS: This European, randomized, double-blind, multicenter trial involved 1.051 patients with lower urinary tract symptoms related to benign prostatic hyperplasia. Patients received sustained release (SR) alfuzosin (n = 358), a selective alpha1-blocker given at a dose of 5 mg twice daily without dose titration; finasteride (n = 344), 5 mg once daily, or both drugs (n = 349), for 6 months. Primary efficacy criteria were symptomatic improvement (International Prostate Symptom Score: I-PSS) and maximum flow rate (Qmax). Safety was assessed by monitoring adverse events. RESULTS: Symptomatic improvement was significantly higher from the 1st month of treatment with SR alfuzosin, alone or in combination; mean changes in I-PSS versus baseline at end-point were -6.3 and -6.1, respectively, compared with -5.2 with finasteride alone (SR alfuzosin vs. finasteride, p = 0.01; combination vs. finasteride, p = 0.03). The percentages of patients with a decrease in I-PSS of at least 50% were 43, 42 and 33% for SR alfuzosin, the combination and finasteride, respectively (SR alfuzosin vs. finasteride, p = 0.008; combination vs. finasteride, p = 0.009). In the overall population, increases in Qmax were greater with SR alfuzosin and the combination, compared with finasteride alone after 1 month of therapy, but changes at end-point were similar in the three treatment groups. In those 47% of patients likely to be obstructed (baseline Qmax <10 ml/s), however, mean increases in Qmax were significantly higher with SR alfuzosin, alone or in combination, whatever the visit. Finasteride, alone or in combination, significantly impaired sexual function. The incidence of postural symptoms was low and similar in the three treatment groups. CONCLUSION: In this 6-month trial, SR alfuzosin was more effective than finasteride, with no additional benefit in combining both drugs.

Clinical uroselectivity: evidence from patients treated with slow-release alfuzosin for symptomatic benign prostatic obstruction.

OBJECTIVE: To assess the safety profile of slow-release (SR) alfuzosin in the treatment of benign prostatic obstruction (BPO), with special attention to orthostatic blood pressure changes, postural symptoms and efficacy. PATIENTS AND METHODS: Two placebo-controlled studies involving 588 patients (292 receiving SR alfuzosin 5 mg twice daily and 296 a placebo) were pooled; 51% of the patients were > or = 65 years of age and 43% had associated cardiovascular disease including hypertension and/or were receiving concomitant antihypertensive drugs. RESULTS: SR alfuzosin was very well tolerated with an overall incidence of adverse events similar to that of placebo (18.5% and 15.8% of patients, respectively) and an overall incidence of withdrawal from therapy for adverse events lower than that of placebo (3.4% and 5.7%, respectively). Adverse events potentially related to vasodilatation were infrequent with SR alfuzosin (the same incidence as with placebo, i.e. 2.7% of patients) and these adverse events occurred mainly during the first month of alfuzosin treatment. The effect on supine blood pressure was minimal. In the subgroups of elderly and hypertensive patients treated with SR alfuzosin, the cumulative incidence of asymptomatic orthostatic hypotension during the first month of treatment was slightly higher than with placebo with no objective consequences on the incidence of adverse events. The clinical efficacy of SR alfuzosin was confirmed by a significant improvement in urinary symptoms and a significant increase in maximum flow rates. CONCLUSION: SR alfuzosin (10 mg/day) can be administered safely without titration in patients with BPO, even in elderly and hypertensive patients. Its favourable benefit/risk ratio allows alfuzosin to be classified as a clinically uroselective alpha 1-blocker. Specific analysis of orthostatic changes in blood pressure is important when assessing the safety profile of an alpha 1-blocker in patients with BPO.

Efficacy and safety of sustained-release alfuzosin 5 mg in patients with benign prostatic hyperplasia. ALGEBI Study Group.

OBJECTIVES: To assess the efficacy and safety of a sustained-release (SR) formulation of alfuzosin, a selective alpha(1)-blocker, in patients with symptomatic benign prostatic hyperplasia (BPH). METHODS: A total of 390 men were randomly assigned to receive SR-alfuzosin (n = 194), 5 mg twice daily without dose titration, or placebo (n = 196) for 12 weeks. Of the patients included, 47% had concomitant cardiovascular disease, mainly hypertension or coronary heart disease. RESULTS: SR-alfuzosin significantly improved urinary symptoms versus placebo assessed using the I-PSS (-31 vs. -18%, p = 0.007) and Boyarsky (-30 vs. -16%, p < 0.001) scores, with a direct correlation between both scores. Maximum flow rate increased significantly with SR-alfuzosin (+2.4 ml/s, i.e. +29%) compared with placebo (+1.1 ml/s, i.e. +14%, p = 0.006). Residual urine was also significantly reduced with SR-alfuzosin. Overall, SR-alfuzosin was as well tolerated as placebo. Nine patients dropped out for adverse events with SR-alfuzosin (4.6%) and 14 (7.1%) with placebo. The incidence of vasodilation-related events (dizziness, postural symptoms, headache) with SR-alfuzosin (3.1%) was similar to that of placebo (3.6%). No first-dose effect was observed compared with placebo. The reduction in supine blood pressure with SR-alfuzosin was minor (< or = 5 mm Hg), both in normotensive and hypertensive patients. CONCLUSION: SR-alfuzosin is an effective treatment of symptoms related to BPH that shows a good safety profile in normotensive and hypertensive patients, without the need of dose titration.

Effect of intravenous alfuzosin on urethral pressure in patients with neurogenic bladder dysfunction. DORALI Study Group.

In order to assess the ability of a single intravenous (i.v.) injection of alfuzosin, a selective alpha-1 blocker, in reducing high urethral tone in patients with symptomatic neurogenic bladder dysfunction (NBD), 163 patients (mean maximal urethral pressure [MUP] 108 +/- 46 cm H2O) were enrolled in a double-blind, placebo-controlled, parallel-group trial and were randomly allocated to receive 0.5 mg (n = 45), 1 mg (n = 41), 2 mg (n = 39) alfuzosin or placebo (n = 38). The decrease in MUP was dose-dependent and statistically significant (P < or = 0.05) for 1 and 2 mg alfuzosin (respectively, 43 +/- 28 cm H2O and 46 +/- 27 cm H2O decreases vs. baseline) in comparison with placebo (23 +/- 30 cm H2O). The 2 mg dose level was the most effective leading to a > or = 30 or 50% decrease in MUP in, respectively, 69 and 44% of patients. The safety of all three alfuzosin dose levels was satisfactory and comparable to placebo. I.v. alfuzosin induces, in a dose-related manner, a clinically significant decrease in urethral pressure in patients with NBD and high urethral tone, and may be safely used as a pharmacological test as part of an urodynamic investigation.

Long-term treatment of benign prostatic hyperplasia with alfuzosin: a 24-30 month survey. BPHALF Group.

OBJECTIVE: To address the long-term results of alfuzosin, an alpha 1-antagonist, in patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: A 6-month, placebo-controlled study involving 518 patients was followed by two successive one-year, open extensions. Only centres who wished to continue the trial participated in the extensions; 131 patients entered the first extension, with 50 continuing into the second year extension. The results of the second year follow-up are presented here. RESULTS: Depending on their initial randomization to either the placebo or alfuzosin arm, patients were treated with alfuzosin for 24 (n = 50) or 30 months (n = 22). The data collected on those 50 patients in comparison to baseline confirmed that the clinical efficacy observed in short/medium-term studies was maintained. A clinically significant improvement in urinary symptoms was observed; the Boyarsky score decreased from 8.7 (+/- 0.3) at baseline to 5.2 (+/- 0.3) at 24 months, with no deterioration in the objective parameters. In patients treated for 30 months (n = 22), symptomatic assessment and urodynamic parameters remained stable, indicating the sustained effectiveness of therapy. No serious or unexpected side-effect related to long-term exposure to alfuzosin was observed. No complications associated with BPH occurred. Two patients (4%) reported dizziness, neither of whom withdrew from the study. In this population, where 40% of patients were receiving concomitant cardiovascular therapy, no clinically significant change in standing systolic blood pressure, diastolic blood pressure or heart rate was apparent between baseline data and those at 24 months. CONCLUSION: These data demonstrate the usefulness of long-term treatment with alfuzosin in patients with uncomplicated, moderate BPH.

Long-term treatment of benign prostatic hyperplasia with alfuzosin: a 12-18 month assessment. BPHALF Group.

In order to assess the efficacy and safety of alfuzosin, an alpha-1 blocker, in symptomatic patients with benign prostatic hyperplasia (BPH), 131 patients who had completed a 6-month placebo-controlled trial conducted on parallel groups entered a 12-month open study; 122 patients were treated with alfuzosin for 12 months and 56 patients for 18 months. After 12 months, all obstructive and irritative symptoms assessed according to the Boyarsky scale were significantly improved, as were peak flow rates in obstructed patients and mean flow rates and residual urine in the whole population. Voiding symptoms showed sustained improvement after treatment for 12 to 18 months. Only 5.3% of patients experienced vasodilatory side effects, none of which led to withdrawal from the study. No side effect related to long-term administration was reported. Alfuzosin has a beneficial effect on voiding symptoms in patients with BPH and can be safely used in long-term administration.

Lumbar disc herniation. Computed tomography scan changes after conservative treatment of nerve root compression.

In 21 patients with computed tomography-diagnosed lumbar herniated nucleus pulposus, nerve root pain resolved after conservative treatment. A subsequent computed tomography scan was performed 6 months or more after presentation. This follow-up computed tomography scan was compared with the initial one. A definite decrease in size of the herniated nucleus pulposus was observed in 14 patients: disappearance in 5, obvious decrease in 5, and moderate decrease in 4. No definite change was observed in seven patients. Major computed tomography scan changes occurred significantly more frequently in large herniated nucleus pulposus than in small ones (p. less than 0.05). This study suggests that large lumbar herniated nucleus pulposus can decrease and even disappear in some patients treated successfully with conservative care.

Urinary flow rates in patients with benign prostatic hypertrophy following treatment with alfuzosin. DUALF Group.

In order to document further the onset of action of alfuzosin, a selective alpha-1 blocker, 93 symptomatic patients with benign prostatic hypertrophy were randomly allocated to a single oral dose of either alfuzosin 1.25 mg or 2.5 mg, or placebo, after a 1-week placebo lead-in period. The effects on flow rates were assessed 1 h 30 min after administration. Peak and mean flow rates were significantly increased in the alfuzosin groups, as compared with placebo, in a dose-dependent manner. After a single intake of placebo, the mean values of these 2 parameters showed little change. The effect on the cardiovascular system (heart rate and blood pressure) was mild. This study indicates that the action of alfuzosin is already present 1 h 30 min after administration.

Alfuzosin for treatment of benign prostatic hypertrophy. The BPH-ALF Group.

To assess the long-term efficacy and safety of alfuzosin, a selective alpha 1-adrenergic antagonist, 518 symptomatic patients with benign prostatic hypertrophy (BPH) were randomised to received either alfuzosin (daily dose 7.5-10 mg) or placebo for 6 months. Obstructive and irritative symptoms, assessed according to the Boyarsky scale, significantly improved in the alfuzosin group compared with the placebo group (p = 0.0004). Fewer patients in the alfuzosin group than in the placebo group dropped out due to lack of efficacy (6.8% vs 14.6%, p = 0.004) and the prevalence of spontaneous acute urine retention was lower in the alfuzosin group (0.4% vs 2.6%, p = 0.04). By 6 months, mean urinary flow rates had increased (p less than 0.05) and residual volume had decreased (p = 0.017) in the alfuzosin group, although the two groups were broadly similar with respect to increase in peak flow rate. The overall incidence of adverse events was similar in the two groups, which led to the withdrawal of 10.8% and 9.0% of patients, respectively. The findings emphasise the magnitude of the placebo response in symptomatic patients with BPH and show that treatment with alpha 1 adrenergic antagonist drugs provides long-lasting improvement in such patients.

Detection of Epstein-Barr virus in epidermal skin lesions of an immunocompromised patient.

Using in-situ hybridizaiton, we showed the presence of the Epstein-Barr (EB) virus genome in epidermal cells from a patient with chronic lymphocytic leukemia and unusual cutaneous lesions characterized clinically by a maculopapular eruption and histologically by epidermal cell degeneration and lymphoid cell infiltration. Such histologic changes are similar to those seen in graft-versus-host disease. The EB virus genome was mainly detected in the basal, germinative cells of the abnormal epithelium. Specimens of our patient's healthy skin were negative. The presence of EB virus DNA in skin lesions was confirmed by polymerase chain reaction adapted for analysis of paraffin-embedded tissue. These findings indicate that EB virus can infect the human epidermis and that the viral infection may produce a distinctive cutaneous disease.

[Peripheral neuropathy and plasmocytic proliferations. Apropos of 17 cases]. / Neuropathie périphérique et proliférations plasmocytaires. A propos de 17 observations.

Seventeen cases of peripheral neuropathy with plasmocytic proliferation were grouped together to analyze the clinical manifestations and evolution of this association of symptoms. The plasmocytic proliferation was 5 times that of multiple myeloma, 9 times that of a solitary bone plasmacytoma and 3 times that of a solitary plasmacytoma. The follow-up lasted 1 to 18 years (mean, 8 years) for solitary plasmacytomas. Other cutaneous and endocrinological symptoms, organomegaly and edema were sometimes present. The evolution was relatively severe, except in 6 patients whose solitary plasmacytomas were successfully treated with radiation. Six patients died 2 to 8 years (mean, 5 years) after the onset of neuropathy as a result of a progression of the neuropathy and/or anasarca (4 cases), or acute leukemia (2 cases) abetted by long-term chemotherapy. The therapeutic approaches available, the nature of the plasmocytic proliferation and its association with the neuropathy and the other symptoms are discussed.

[Meningococcal arthritis (serogroup A) contracted during a pilgrimage to Mecca]. / Arthrite méningococcique (sérogroupe A) contractée au cours d'un pélerinage à la Mecque.

Case report of one meningococcal arthritis (serogroup A) acquired during Mecca pilgrimage (August 1987). It was the first case of an outbreak of twenty infections due to Neisseria meningitidis groupe A reported in France from August 1987 to March 1988.

[Periarteritis nodosa complicated by intrapancreatic vascular rupture]. / Périartérite noueuse compliquée d'une rupture vasculaire intra-pancréatique.

Clinical pancreatic manifestations are unusual in polyarteritis nodosa. A case of intrapancreatic hemorrhage due to vascular rupture occurring during the course of histologically proven polyarteritis nodosa is described. The patient presented with massive hemoperitoneum requiring emergency laparotomy. Splenopancreatectomy was performed to control bleeding. Steroid therapy was continued during the postoperative course, with favorable outcome. The mechanism of vascular rupture is not clear, but is probably related to focal arteritis with consequent infarction. No ruptured microaneurysm was found in this case.

Solitary plasmacytoma of the spine. Long-term clinical course.

The data for 19 patients with solitary plasmacytoma of the spine were reviewed with regard to clinical course and prognosis (median follow-up, 96 months). Eight patients presented with spinal cord compression. A monoclonal immunoglobulin was initially detected in seven of 15 evaluable patients. Treatment included radiotherapy (18 of 19) and/or surgery (11 of 19) and chemotherapy (eight of 19). Spinal cord compression was reversed in every patient. The expected survival rate was 85% at 10 years after diagnosis. Local recurrence or dissemination was observed in 13 patients. It occurred within 5 years of diagnosis in 11 patients and was localized (that is, local recurrence or single bone metastasis) in eight patients. It was always associated with the appearance or an increase of the M component. Dissemination frequently had a "metastatic" pattern with no diffuse bone marrow plasmacytosis. The incidence of local recurrence (five patients) and leukemia (four patients) was high. Local recurrence and/or dissemination were significantly more frequent in patients with the M component at diagnosis than in those without it (P less than 0.05; relative risk, R = 4). The effectiveness of surgery and chemotherapy combined with radiotherapy is also discussed.