Clinical trial: the efficacy of open-label prucalopride treatment in patients with chronic constipation - follow-up of patients from the pivotal studies.

BACKGROUND: Prucalopride is approved in Europe for symptomatic treatment of chronic constipation in women with inadequate relief from laxatives. AIM: To evaluate efficacy of prucalopride during long-term treatment of patients with chronic constipation. METHODS: Patients from three pivotal double-blind, placebo-controlled, 12-week studies with prucalopride could continue treatment in open-label studies up to 24 months. Efficacy was evaluated every 3 months using the Patient Assessment of Constipation-Quality of Life (PAC-QOL) satisfaction scale. Laxative use and reasons for study discontinuation were recorded. RESULTS: Eighty-six percent of patients who completed the pivotal studies continued prucalopride treatment in the open-label studies (n = 1455, 90% female). Improvement in average PAC-QOL satisfaction score observed after 12-week, double-blind prucalopride was maintained during open-label treatment for up to 18 months; in each 3 month period, 40-50% of patients did not use any laxatives. Most frequent adverse events (AEs) resulting in discontinuation were gastrointestinal events (3.3%) and headache (1.0%). Only 10% of patients who had normalized bowel function on prucalopride at the end of pivotal trials discontinued due to insufficient response during open-label treatment. CONCLUSION: Satisfaction with bowel function is maintained for up to 18 months of treatment with prucalopride. Gastrointestinal events and headache cause discontinuation of prucalopride treatment in ∼5% of patients (ClinicalTrials.gov identifiers: NCT01070615 and NCT00987844).

Safety assessment of prucalopride in elderly patients with constipation: a double-blind, placebo-controlled study.

Chronic constipation is common among nursing home residents. The aim of this study was to evaluate safety, tolerability and pharmacokinetics of the selective 5HT(4) receptor agonist prucalopride in elderly, chronically constipated patients in nursing homes. A multicentre, phase II, randomized, double-blind dose-escalation study in 89 elderly constipated nursing home residents treated with placebo, 0.5, 1 or 2 mg prucalopride once daily for 28 days was analysed. Adverse events, vital signs, ECG, Holter monitor and pharmacokinetics were assessed (Clinicaltrials.gov identifier: NCT00627692). Patients' mean age was 83 years; 88% had a history of cardiovascular diseases. Most frequent adverse events, at least possibly related to prucalopride, were diarrhoea and abdominal pain. Relative to placebo, there were no differences in vital signs, ECG corrected QT interval, ECG morphology parameters, or incidence of supraventricular or ventricular arrhythmias on Holter monitoring. Plasma prucalopride concentrations increased proportionally with administered dose. Prucalopride up to 2 mg once daily for 4 weeks was safe and well-tolerated by constipated elderly patients, with no differences vs placebo in ECG or a range of Holter-monitoring parameters.

Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives.

OBJECTIVE: To determine the efficacy, impact on quality of life (QOL) and safety of prucalopride, a selective, high-affinity 5-HT(4) receptor agonist, in patients with chronic constipation. METHODS: In this multicentre, randomised, placebo controlled, parallel-group, phase III study, patients with chronic constipation (two or fewer spontaneous complete bowel movements (SCBM)/week) received 2 mg or 4 mg prucalopride or placebo, once daily, for 12 weeks. The primary efficacy endpoint was the proportion of patients reaching three or more SCBM/week. The key secondary efficacy endpoint was the proportion of patients having an increase of one or more SCBM/week. The primary QOL endpoint was the patient assessment of constipation QOL satisfaction subscale score. Safety parameters included adverse events, laboratory values and cardiovascular events. RESULTS: Efficacy was evaluated over 713 patients. Averaged over 12 weeks, higher proportions of patients on prucalopride 2 mg (19.5%; p<0.01), 4 mg (23.6%; p<0.001) had three or more SCBM/week (or normalisation of bowel function) compared with placebo (9.6%). Similar results were seen in the subgroup (83%) of patients dissatisfied with previous laxative treatment. Both doses of prucalopride also significantly improved secondary efficacy and QOL endpoints, including the proportion of patients with an increase of one or more SCBM/week, evacuation completeness, perceived disease severity and treatment effectiveness and QOL. Prucalopride 4 mg significantly reduced the need for straining versus placebo (p<0.05). The most frequent treatment-related adverse events were headache and diarrhoea. Both doses of prucalopride were safe and well tolerated. CONCLUSION: Prucalopride significantly and consistently improved bowel function, associated symptoms and satisfaction in chronically constipated patients.

Identification and molecular characterization of a novel splice-site mutation (G1205C) in the SQSTM1 gene causing Paget's disease of bone in an extended American family.

Paget's disease of bone (PDB) is a common late-onset bone disorder characterized by focal areas of abnormal bone remodeling. Positional cloning efforts resulted in the identification of seven genetic loci (PDB1-7) with putative involvement in the pathogenesis of PDB. Meanwhile, the PDB-causing gene from the PDB3 region on chromosome 5q35 has been identified as the SQSTM1 gene. All mutations identified in this gene so far are located in or close to the ubiquitin-associated (UBA) domain of the protein. In 2001, we reported genotyping results of genetic markers located in the PDB3 region in an extended American family, indicating the involvement of the PDB3 locus. Here, we report the identification of a novel mutation (G1205C) in the SQSTM1 gene in this family. The G1205C mutation is located in the splice donor site of intron 7 and reverse-transcription polymerase chain reaction experiments showed that the presence of the C allele results in the production of two abnormal mRNA transcripts. Translation of the first transcript would result in a protein that lacks amino acids 351-388, including 26 amino acids of the second PEST domain in addition to two amino acids of the UBA domain. The second mutant mRNA transcript could result in a truncated protein (390X) that lacks almost the complete UBA domain. PDB mutations that disrupt the function of the PEST domain of SQSTM1 have not been reported before, so probably the pathogenic effect of both transcripts resides in the disruption of the ubiquitin-binding properties of the protein.

Evaluation of the role of the SQSTM1 gene in sporadic Belgian patients with Paget's disease.

A positional cloning effort in French Canadian families with Paget's disease of bone (PDB) resulted in the identification of a mutation in the sequestosome1 (SQSTM1) gene in a subset of both familial and sporadic PDB cases. This was confirmed in samples of mainly United Kingdom (UK) origin. In this study, we performed both mutation analysis and association studies in order to evaluate the role of this gene in a collection of isolated Belgian PDB patients. A mutation in the SQSTM1 gene was found in only 6 of 111 patients (5.4%). In all cases it involves the P392L mutation, previously shown to be common in both familial and sporadic cases. To perform association studies, we selected 8 single nucleotide polymorphisms (SNPs) and looked for linkage disequilibrium (LD) between these. Haplotype analysis indicated that typing of 3 Tag SNPs (IVS1 + 633A/C, IVS5 - 23A/G, and 976A/G) enables us to identify the most common haplotypes. Association studies for the 3 selected SNPs, based on 105 PDB cases without a SQSTM1 mutation and 159 control individuals, did not support a possible influence of natural variants in the SQSTM1 gene either on the pathogenesis of PDB or on the disease severity. In conclusion, our study confirms that the P392L mutation is a recurrent mutation causing PDB in different populations. We were not able to show an association between SQSTM1 polymorphisms and PDB in our population but this clearly needs to be extended to other populations. The presented identification of haplotype Tag SNPs will be of major help for such studies.

Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease.

Our aim was to determine the usefulness of circulating oxidized low density lipoprotein (LDL) in the identification of patients with coronary artery disease (CAD). A total of 304 subjects were studied: 178 patients with angiographically proven CAD and 126 age-matched subjects without clinical evidence of cardiovascular disease. The Global Risk Assessment Score (GRAS) was calculated on the basis of age, total and high density lipoprotein cholesterol, blood pressure, diabetes mellitus, and smoking. Levels of circulating oxidized LDL were measured in a monoclonal antibody 4E6-based competition ELISA. Compared with control subjects, CAD patients had higher levels of circulating oxidized LDL (P<0.001) and a higher GRAS (P<0.001). The sensitivity for CAD was 76% for circulating oxidized LDL (55% for men and 81% for women) compared with 20% (24% for men and 12% for women) for GRAS, with a specificity of 90%. Logistic regression analysis revealed that the predictive value of oxidized LDL was additive to that of GRAS (P<0.001). Ninety-four percent of the subjects with high (exceeding the 90th percentile of distribution in control subjects) circulating oxidized LDL and high GRAS had CAD (94% of the men and 100% of the women). Thus, circulating oxidized LDL is a sensitive marker of CAD. Addition of oxidized LDL to the established risk factors may improve cardiovascular risk prediction.

Is transcranial Doppler useful in the detection of internal carotid artery cross-clamp intolerance?

The aim of this study was to test the hypothesis that a drop in the systolic blood flow velocity in the middle cerebral artery of 70% or more, measured by transcranial Doppler, is a better criteria in the detection of cross-clamp intolerance than electroencephalogram (EEG) and somatosensory evoked potential (SSEP) monitoring. After exclusion of patients with a recent stroke, urgent procedures and combined procedures, a transcranial Doppler with compression test was scheduled in 85 patients. In 13 patients the drop was 70% or more and in these patients a transcranial Doppler was also performed during the reconstruction of the internal carotid artery (the study group) under general anaesthesia. A shunt was used because of EEG and SSEP abnormality in one patient. No changes were observed in the remaining patients and no intraoperative strokes were seen. The transcranial Doppler monitoring was unreliable in three patients. During cross-clamp, the systolic blood flow velocity in the middle cerebral artery dropped less than 70% in four and 70% or more in six patients. It is concluded that using a drop of 70% or more of the systolic blood flow velocity in the middle cerebral artery during internal carotid artery cross-clamp, as an indicator of cross-clamp intolerance, will lead to unnecessary shunting.

Doppler flowmetry in the planning of perforator flaps.

Perforator flaps have become the first choice in free flap reconstruction of contour defects or skin and fat replacement in our department. The Deep Inferior Epigastric Perforator (DIEP), the Superior Gluteal Artery Perforator (S-GAP) and the Thoracodorsal Artery Perforator (TAP) flaps are now routinely used. By evaluating the vascular anatomy of these flaps preoperatively, we intend to improve our surgical strategy so that these operative procedures can proceed in a faster and safer way. In this study, the results of the colour Duplex scanning in 50 consecutive DIEP flap patients are reviewed and evaluated for their sensitivity and positive predictive value. Also the preoperative information from unidirectional Doppler flowmetry in 30 S-GAP flaps and 11 TAP flaps is evaluated for its reliability. Due to the variable vascular anatomy of the lower abdominal wall and the dorso-lateral thoracic wall we now prefer using the colour Duplex scanning for planning the DIEP and TAP flaps. The more constant course of the branches of the superior gluteal artery allows us to use the easier and cheaper unidirectional Doppler flowmetry for planning the S-GAP flap.

The clinical value of duplex surveillance following internal carotid artery reconstruction.

BACKGROUND: The purpose of this retrospective analysis was to evaluate the benefit of a yearly duplex ultrasonography of both the reconstructed and the contralateral internal carotid artery (ICA). METHODS: From 1985 to 1994, 1210 unilateral, primary ICA reconstructions were performed. Although these patients received yearly invitations, duplex follow-up was not available in 114 patients (9%). RESULTS: At 5 years a stenosis of 50% or more was found in 9% and at 10 years in 14% of patients. During the follow-up period 20 patients developed a stenosis of 80-99%. Ten patients had a redo-procedure. The others remained asymptomatic, even though one patient developed an occlusion. A stroke occurred in 96 patients. 58 of these had no significant stenoses. 57% of all patients had no significant contralateral lesion at the time of the first procedure. In only 4% of these a contralateral CAE was performed during the follow-up. CONCLUSIONS: In view of the above data, we would conclude that the clinical benefit of duplex surveillance is doubtful.

Predictive value of nailfold capillaroscopy in the diagnosis of connective tissue diseases.

We revised the clinical files of 326 patients who underwent nailfold capillaroscopy. These patients could be subdivided into 4 groups: I: patients with clinical suspicion of connective tissue disease, II: patients with isolated Raynaud's phenomenon, III: patients with existing connective tissue disease, IV: patients with acrocyanosis, chronic pernio or related disorders. The presence of megacapillaries was noted. The sensitivity of their presence for the various categories of connective tissue disease was as follows: systemic sclerosis (n = 11): 100%, CREST (n = 15): 73%, MCTD (n = 9): 56%, dermatomyositis (n = 7): 86%. Nineteen patients with megacapillaries had no final diagnosis of connective tissue disease (specificity 93.3%). The positive predictive value of the presence of megacapillaries for a scleroderma spectrum disorder (SSD) was 63.5% and the negative predictive value of a normal capillaroscopy 96.7%. We conclude that nailfold capillaroscopy can be advised to rule out SSD's.

Assessment of the patency of deep leg veins with duplex.

To evaluate the accuracy of venous duplex, results obtained in 101 patients are compared with venography. A first group consisted of 48 patients with clinically suspected deep vein thrombosis. In 30 of them a positive duplex scan was obtained and all had subsequently a positive venography. Eighteen patients with a normal duplex scan had a normal venography. Another group of 53 patients were tested preoperatively for varicose vein surgery. No obstruction of the venous system was withheld with duplex but 3 patients had an old thrombosis on venography. Thus duplex is a highly reliable method to detect proximal thrombosis in clinically suspected patients but detection of late sequelae of thrombosis may be more difficult.

Aorto-femoral reconstruction and sexual function: a prospective study.

The influence of aorto-femoral (AF) Dacron reconstruction on sexual function and pelvic circulation was studied prospectively in 62 male patients with aorto-iliac occlusive disease. Erectile function remained unchanged in 77%. Improvement or deterioration was seen in 11.3% and 20.5% of the cases respectively. Impotence occurred in only one patient (6%) with normal function preoperatively but in 31% of those presenting with impaired erection. Pelvic circulation, as reflected by the penile brachial index (PBI), was not affected in 74%, increased in 11% and decreased in 15% of the reconstructions. Pelvic circulation was at least preserved in 90% after an end-to-side proximal anastomosis and in 82% after an end-to-end anastomosis. Since fluctuations in sexual function could be related to changes in PBI in only 36% of the cases it is concluded that sexual disorders after AF surgery are due to a combination of disturbed pelvic haemodynamics and interruption of the preaortic autonomic plexus. Patients with impaired erectile function are especially at risk of a deterioration and the possibilities of restoring erectile function in patients with aorto-iliac stenosis by isolated AF reconstruction are limited.

Aortofemoral reconstruction for multilevel disease: a prospective hemodynamic study.

A prospective study was undertaken to evaluate the clinical and hemodynamic effects of aortofemoral Dacron reconstruction in patients with multilevel disease (i.e. aortoiliac and femoropopliteal occlusive disease). Thirty nine patients underwent, apart from clinical evaluation, segmental plethysmography and Doppler pressures before operation, immediately after operation and again at 3 and 6 months. All patients improved by the reconstruction, but 12 (31%) continued to complain of disabling claudication during normal daily activities. The mean ankle pressure and thigh pressure index improved by 37.5%. This was accompanied by a decrease of peak flow time, an increase of peak flow and an improved recovery during reactive hyperemia. Furthermore an additional significant rise of the ankle pressure index was noted between 3 and 6 months. Continuing claudication was always associated with both initial and late hemodynamic failure (the criterium for hemodynamic success was defined as an increase of the ankle pressure index with more than 0.1). Hemodynamic success resulted unvariably in clinical success. However 4 patients were clinically symptomfree, although they had to be classified as hemodynamic failures. It is concluded that a significant number of patients fail to obtain complete relief after proximal reconstruction. Preoperative hemodynamic studies may provide additional information, but hemodynamic and clinical results do not always correlate with each other.

Controlled trial of suloctidil in intermittent claudication.

Forty-five patients with intermittent claudication were first treated with placebo tablets for 3 months and then randomly allocated to double-blind therapy with either suloctidil or placebo for 6 months. Walking distance improved significantly in both groups during the 3 months of placebo treatment. During the 6 months of double-blind treatment with a further significant improvement occurred only in the placebo group when all patients were analyzed. However, when patients who stopped for reasons unrelated to claudication such as angina and exhaustion during repeated walking tests were eliminated, only suloctidil-treated patients improved significantly. The evolution of leg flow and distal pressure was similar in the two treatment groups whether all legs or only legs with abnormal flow and pressure values were considered. By contrast, when the analysis was limited to legs with claudication pain, a significant improvement occurred only in the suloctidil-treated group. These findings suggest that suloctidil may improve the claudication symptoms of patients with chronic arterial obstructive disease and in particular the perfusion of legs experiencing claudication pain. However, the clinical significance of this improvement appears limited.