Functional improvement and correlations with symptomatic improvement in adults with attention deficit hyperactivity disorder receiving long-acting methylphenidate.

BACKGROUND: Data on the relationship between core symptoms and daily functioning in adults with attention deficit hyperactivity disorder (ADHD) are limited. Daily functioning was assessed as part of an open-label extension, and associations with symptom scores were evaluated. METHOD: After a 5-week double-blind study with adults with ADHD receiving osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) 18, 36 or 72 mg/day, or placebo, participants were eligible for a 7-week open-label extension in which all patients received OROS MPH. Data for the Conners' Adult ADHD Rating Scale - Observer: Screening Version (CAARS-O:SV) (primary endpoint) have been presented previously. Secondary endpoints included the observer self-reported short version of the CAARS (CAARS-S:S) and the Clinical Global Impressions - Severity Scale (CGI-S). Daily functioning and quality of life were assessed using the Sheehan Disability Scale (SDS) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) respectively. In post-hoc analyses, changes in CAARS-O:SV were evaluated in subgroups. Relationships between symptom and functional outcomes were evaluated in a multivariate regression analysis. RESULTS: A total of 370 patients entered the open-label extension. Significant improvements from baseline in CAARS-O:SV were similar regardless of sex, ADHD subtype, prior treatment or psychiatric co-morbidity. Significant improvements from double-blind baseline were also seen for the CAARS-S:S, CGI-S, SDS and Q-LES-Q. Improvements in the CAARS-O:SV Hyperactivity/Impulsivity subscale were associated with improvements in SDS total and subscale scores, and in the Q-LES-Q score at open-label endpoint. Improvements in CAARS-O:SV Inattention subscale and CGI-S scores were not significantly associated with functional changes. CONCLUSIONS: Improvements in ADHD symptoms relating to hyperactivity and impulsivity in adults receiving OROS MPH are associated with improvements in daily functioning and quality of life.

Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study.

The aim of this study was to evaluate the efficacy and tolerability of topiramate for the prevention of chronic migraine in a randomized, double-blind, placebo-controlled trial. Chronic migraine is a common form of disabling headache presenting in headache subspecialty practice. Preventive treatments are essential for chronic migraine management, although there are few or no controlled empirical trial data on their use in this patient population. Topiramate is approved for the prophylaxis of migraine headache in adults. Patients (18-65 years) who experienced chronic migraine (defined as > or =15 monthly migraine days) for > or =3 months prior to trial entry and had > or =12 migraine days during the 4-week (28-day) baseline phase were randomized to topiramate or placebo for a 16-week, double-blind trial. Topiramate was titrated (25 mg weekly) to a target dose of 100 mg/day, allowing dosing flexibility from 50 to 200 mg/day, according to patient need. Existing migraine preventive treatments, except for antiepileptic drugs, were continued throughout the trial. The primary efficacy measure was the change in number of migraine days from the 28-day baseline phase to the last 28 days of the double-blind phase in the intent-to-treat population, which consisted of all patients who received at least one dose of study medication and had one outcome assessment during the double-blind phase. Health-related quality of life was evaluated with the Migraine Specific Quality of Life Questionnaire (MSQ, Version 2.1), the Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires, and tolerability was assessed by adverse event (AE) reports and early trial discontinuations. Eighty-two patients were screened. Thirty-two patients in the intent-to-treat population (mean age 46 years; 75% female) received topiramate (mean modal dose +/- SD = 100 +/- 17 mg/day) and 27 patients received placebo. Mean (+/-SD) baseline number of migraine days per 4 weeks was 15.5 +/- 4.6 in the topiramate group and 16.4 +/- 4.4 in the placebo group. Most patients (78%) met the definition for acute medication overuse at baseline. The mean duration of treatment was 100 and 92 days for topiramate- and placebo-treated patients, respectively. Study completion rates for topiramate- and placebo-treated patients were 75% and 52%, respectively. Topiramate significantly reduced the mean number of monthly migraine days (+/-SD) by 3.5 +/- 6.3, compared with placebo (-0.2 +/- 4.7, P < 0.05). No significant intergroup differences were found for MSQ and HIT-6. MIDAS showed improvement with the topiramate treatment group (P = 0.042 vs. placebo). Treatment emergent adverse events were reported by 75% of topiramate-treated patients (37%, placebo). The most common AEs, paraesthesia, nausea, dizziness, dyspepsia, fatigue, anorexia and disturbance in attention, were reported by 53%, 9%, 6%, 6%, 6%, 6% and 6% of topiramate-treated patients, respectively, vs. 7%, 0%, 0%, 0%, 0%, 4% and 4% of placebo-treated patients. This randomized, double-blind, placebo-controlled trial demonstrates that topiramate is effective and reasonably well tolerated when used for the preventive treatment of chronic migraine, even in the presence of medication overuse.

Add-on topiramate in the treatment of refractory partial-onset epilepsy: clinical experience of outpatient epilepsy clinics from 11 general hospitals.

An open, prospective, observational study was performed to assess efficacy and adverse-event profile of topiramate as add-on therapy in epilepsy. Outpatient neurology clinics from 11 general hospitals in Greece participated in the study. In total, 211 patients with treatment resistant partial-onset seizures who met the inclusion criteria, were studied. After baseline evaluation, topiramate was given at a target dose of 200mg/day over a 1-month titration period. In the subsequent maintenance period, the topiramate dose could be varied according to the clinical results. Patients were followed for in total 6 months, with monthly visits and regular physical, neurological and laboratory examinations. Seizure frequencies decreased to 35--40% of baseline values following 3 months of treatment and remained relatively constant thereafter. The average monthly seizure frequency over the 6-month study period was 4.61, compared to 9.21 at baseline. The number of responders (patients with at least 50% reduction in seizure frequency) followed a similar pattern, i.e., increase during the first 3 months levelling off at a final 80--85% response rate. Of those completing the study, 30% had been seizure-free for at least 3 months and 12% for 5 months. Topiramate was well tolerated, no deviations in laboratory values were found. Adverse events appeared to occur less frequently, and antiepileptic effects were more pronounced in this prospective open-label study than in earlier reports from randomised controlled trials. The nature of the patient population and the application of individualised dose optimisation are proposed as contributing factors to explain the favourable results of this study.

Effects of prucalopride on colonic transit, anorectal function and bowel habits in patients with chronic constipation.

BACKGROUND: There is a need for better tolerated drugs to normalize bowel function in chronic constipation. Prucalopride is a highly selective, specific, serotonin4 receptor agonist with enterokinetic properties. AIM: To evaluate the effects of prucalopride on bowel function, colonic transit and anorectal function in patients with chronic constipation. METHODS: Twenty-eight patients were enrolled in this double-blind, placebo-controlled, crossover study (prucalopride: 1 mg, n=12; 2 mg, n=16). Patients kept a bowel function diary. Colonic transit times and anorectal function (anal manometry, rectal sensitivity and rectal compliance) were assessed. RESULTS: Prucalopride (1 mg) compared to placebo significantly increased the mean number of spontaneous complete, spontaneous and all bowel movements per week. Prucalopride (1 mg) significantly decreased the percentage of bowel movements with hard/lumpy stools and straining and increased the urge to defecate. Prucalopride (1 and 2 mg) decreased the mean total colonic transit time by 12.0 h (prucalopride 42.8 h vs. placebo 54.8 h; P=0.074). No statistically significant effects were found in any of the anorectal function parameters. Prucalopride was well tolerated. There were no clinically relevant changes in standard safety parameters. CONCLUSIONS: Prucalopride significantly improves stool frequency and consistency, and the urge to defecate, and may decrease colonic transit times in patients with chronic constipation.

Standard-dose lansoprazole is more effective than high-dose ranitidine in achieving endoscopic healing and symptom relief in patients with moderately severe reflux oesophagitis. The Dutch Lansoprazole Study Group.

BACKGROUND: In the treatment of reflux oesophagitis, H2-receptor antagonists are still widely used in spite of the apparent higher efficacy of proton pump inhibitors. In an attempt to compensate for the lower efficacy, H2-receptor antagonists are now increasingly being used at a higher dose. OBJECTIVE: To assess whether or not standard-dose lansoprazole (30 mg o.d.) is more effective than high-dose ranitidine (300 mg b.d.) in moderately severe reflux oesophagitis (grades II-III). METHODS: Lansoprazole or ranitidine was given to 133 patients for 4-8 weeks in a double-blind, randomized, parallel group, multicentre trial. RESULTS: The percentage of patients with endoscopically-verified healing was significantly higher on lansoprazole than on ranitidine both after 4 weeks (79% vs. 42%) and 8 weeks (91% vs. 66%), though smoking had a negative impact on oesophagitis healing with lansoprazole. Heartburn, retrosternal pain and belching improved significantly better with lansoprazole than with ranitidine, as did the patient-rated overall symptom severity. Relief of heartburn appeared somewhat faster with ranitidine, but was more pronounced with lansoprazole. The number of patients with adverse events was similar in both treatment groups. CONCLUSION: Standard-dose lansoprazole is better than high-dose ranitidine in moderately severe reflux oesophagitis.

The influence of cisapride and clarithromycin on QT intervals in healthy volunteers.

OBJECTIVE: Recently a few cases of long QT syndrome were reported during treatment with cisapride. In most of these cases, risk factors for cardiac arrhythmias or pharmacologic interactions might have been involved, and the role of cisapride remained unclear. Macrolides such as clarithromycin potentially interact with the metabolic elimination of cisapride and have overlapping indication areas. We therefore studied whether combined treatment with clarithromycin and cisapride leads to pharmacokinetic changes and increased QT intervals. METHODS: The study was an open, randomized, 2-way crossover study with washout periods of 1 week. Twelve healthy volunteers were recruited. Treatments were cisapride (10 mg 4 times a day) for 10 days with concomitant clarithromycin (500 mg twice a day) from days 6 through 10, or clarithromycin (500 mg twice a day) for 10 days combined with cisapride (10 mg 4 times a day) from days 6 through 10. Frequent ECG recordings were performed for 24 hours before drug treatment (baseline). After 5 days of monotherapy and combination therapy, frequent ECG recordings and assessments of plasma drug levels were performed for 24 hours. RESULTS: Clarithromycin alone was associated with a minimal increase in QTc intervals. Monotherapy with 10 mg cisapride 4 times a day led to a concentration-dependent QTc elevation, amounting to 6 ms during steady state. Combination of cisapride and clarithromycin caused an average QTc increase of 25 ms above pretreatment values and 3-fold increases in cisapride concentrations. CONCLUSIONS: QTc elevations after cisapride or clarithromycin alone remained within the normal range of diurnal variation. Coadministration of cisapride and clarithromycin produced a substantial QT prolongation. The data support the recently purported interaction between cisapride and clarithromycin and thus the filed contraindication to combine these drugs.

Effect of ketanserin on intraoperative blood loss during total hip arthroplasty in elderly patients under general anaesthesia.

We have studied the effect of ketanserin, a selective serotonin S2-receptor antagonist, on surgical bleeding in a double-blind, placebo-controlled study in elderly patients undergoing total hip arthroplasty. One group of patients (n = 9) received ketanserin 10 mg i.v. followed by an infusion of 0.075 mg kg-1 h-1. The second group (n = 8) received placebo. Both groups were comparable with regard to age, height and body weight. Mean intraoperative blood loss was 454 ml with ketanserin and 894 ml with placebo (P = 0.004; Wilcoxon two-sample test). Mean duration of the operation was less with ketanserin (112 min) than with placebo (134 min) (P = 0.004), but rate of blood loss was also less with ketanserin (4.1 vs 6.7 ml min-1; P = 0.03). In the ketanserin group, mean arterial pressures tended to be less than in the placebo group. Reductions in central venous pressure were similar in both groups. There were no complications in relation to the use of ketanserin.

Ketanserin pharmacokinetics in patients with renal failure.

1. The pharmacokinetics of ketanserin and its major metabolite ketanserin-ol were investigated after a single oral dose of 40 mg and after chronic oral administration of 20 or 40 mg twice daily for 10 days in 12 patients with chronic renal insufficiency of whom six were on intermittent haemodialysis. Plasma protein binding of ketanserin was measured in these 12 patients and in eight healthy volunteers. 2. In both dialysis and non-dialysis patients the terminal half-life of ketanserin (mean +/- s.d.) was prolonged compared with that reported previously for healthy volunteers (28 +/- 4 h vs 18 +/- 4 h). This may be explained by a lowered renal clearance of ketanserin-ol from which ketanserin is partly regenerated. 3. In patients with chronic renal insufficiency plasma ketanserin concentrations were similar to those found in healthy subjects after the same dose. Plasma ketanserin-ol concentrations were elevated, resulting in a raised AUC ratio of ketanserin-ol to ketanserin as compared with healthy individuals (7.3 +/- 4.0 vs 3.2 +/- 0.7). 4. Urinary excretion of ketanserin was negligible in both dialysis and non-dialysis patients, and ketanserin-ol excretion was markedly lowered. 5. The plasma protein binding of ketanserin was slightly reduced in comparison with healthy volunteers (93.7 +/- 1.0% vs 95.0 +/- 0.2%). 6. A dose regimen of 20 mg twice daily appeared to be well tolerated in spite of less plasma binding in renal failure.

Oral dosing with ketanserin to control high blood pressure in the elderly.

Ketanserin is the prototype of a new class of antihypertensive drugs based on a selective blockade of serotonin S2 receptors. A number of controlled trials have indicated that ketanserin is more effective in older than in younger subjects and that, in the elderly, ketanserin may be even more effective than other antihypertensive drugs. We set up a large multicenter trial to compare the two most common dosages of ketanserin (20 mg and 40 mg twice daily) in patients of 60 years of age and over. In these patients, blood pressures were elevated systolically (SBP greater than or equal to 160 mmHg), diastolically (DBP greater than or equal to 95 mmHg), or both, and any existing antihypertensive medication was continued at a constant dosage. The total duration of the trial was 3 months and monthly control visits were held. Throughout the Netherlands, 252 general practitioners participated in the trial, which included 462 evaluable patients. After 1 month of open treatment with 20 mg ketanserin twice daily, blood pressure was found to be fully normalized in 18% of patients, while the proportion of patients with both systolic and diastolic hypertension was reduced from 89% to 50%. In three out of four patients, an adequate and maximal fall in blood pressure was reached only after 2-3 months of treatment. In such patients, raising the ketanserin dose from 20 mg to 40 mg twice daily did not result in any faster or improved antihypertensive response. A number of symptoms related to peripheral circulatory disturbances, or possibly to hypertension itself, markedly improved during oral treatment with ketanserin.

Effects of intra-arterial ketanserin in Raynaud's phenomenon assessed by 99MTc-pertechnetate scintigraphy.

The severity of the peripheral vasopastic condition in 10 patients with Raynaud's phenomenon was investigated using scintigraphy of both hands. 99MTc-pertechnetate was used as a diffusable tracer and scintigrams were recorded with normal hand skin temperature and following immersion of the hands in ice-cold water. Cold provocation resulted in a marked reduction of the rate of blood inflow and tissue perfusion in affected hands. The selective peripheral S2-antagonist ketanserin and placebo were administered intra-arterially according to a double-blind cross-over design. As compared to placebo, ketanserin significantly improved the rate of inflow following cold provocation, and it increased tissue perfusion in the hands of the patients to values normally observed in healthy individuals. The results support the use of ketanserin in the treatment of Raynaud's phenomenon.

[125I]SCH 23982: the ligand of choice for identifying the D-1 dopamine receptor.

[125I]SCH 23982, [125I]8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol, binds reversibly and with high affinity (Kd = 0.7 +/- 0.05 nM) to specific binding sites (maximum binding = 108 +/- 3.5 fmol/mg) in the caudate nucleus of the rat brain. The caudate binding site displays pharmacological properties similar to the D-1 receptor; furthermore, the site has a low affinity for drugs favoring the D-2 receptor. GTP diminishes the affinity of dopamine, a D-1 agonist, but not SCH 23390, a D-1 antagonist, for the caudate binding site. The iodinated ligand discriminates between the D-1 and the D-2 dopamine receptors: the neurointermediate lobe of the rat pituitary gland, a tissue rich in D-2 dopamine receptors, possesses less than 4% of the specific binding sites in the caudate. Because [125I]SCH 23982 exists at a higher specific activity than [3H]SCH 23390, a ligand used previously to identify the D-1 receptor, and because the results obtained with the iodinated ligand are otherwise similar to those obtained with the [3H]SCH 23390, [125I]SCH 23982 is the ligand of choice for identifying the D-1 receptor.

The effectiveness of yohimbine in blocking rat central dopamine autoreceptors in vivo.

The influence of various alpha-adrenoceptor antagonists (10 mg/kg i.p.) upon the rate of turnover of dopamine (DA) in the rat brain was investigated. Taking the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as a measure of the rate of DA turnover, it was found that prazosin and phenoxybenzamine decreased, whereas piperoxane and yohimbine increased the turnover rate both in the corpus striatum and in the tuberculum olfactorium. Azapetine, phentolamine and tolazoline as well as the beta-adrenoceptor antagonist propranolol were without a significant effect, whereas the DA antagonist haloperidol increased DOPAC and HVA levels and decreased the levels of DA itself. The possibility that the yohimbine-induced increase in the DA turnover rate was produced by a direct blockade of DA autoreceptors, was investigated under conditions where influences other than those elicited via DA autoreceptors are thought to be eliminated, i.e. in rats treated with reserpine or gamma-butyrolactone (GBL). In rats that were pretreated with reserpine, yohimbine (10 mg/kg i.p.) was found to be ineffective in antagonizing the reduction of the accumulation of 3,4-dihydroxyphenylalanine (DOPA) following decarboxylase inhibition, that was produced by the DA agonist apomorphine (2.0 mg/kg i.p.). In rats pretreated with reserpine, yohimbine (10 mg/kg i.p.) was also ineffective in antagonizing the reduction of the DOPAC and HVA levels produced by apomorphine (2.0 mg/kg i.p.), but it was effective in antagonizing the reduction of the HVA level that was produced by the selective DA autoreceptor agonist N,N-di-n-propyl-7-hydroxy-2-aminotetralin (DP-7-AT, 1.0 mg/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo dopamine autoreceptor selectivity appears to be critically dependent upon the aromatic hydroxyl position in a series of N,N-disubstituted 2-aminotetralins.

The potencies of a number of 2-aminotetralin derivatives as centrally acting dopamine (DA) receptor agonists were investigated using the reversal of the gamma-butyrolactone-induced increase in rat central DA biosynthesis rate as a measure of potency at DA autoreceptors and the reversal of the reserpine-induced immobility of mice as a measure of postsynaptic DA receptor stimulating potency. The results indicated that the compounds fell into two separate groups depending on their effectiveness in the postsynaptic test model. High postsynaptic effectiveness was achieved with compounds bearing a hydroxyl group at the 5 position of the aminotetralin structure, whereas aminotetralins lacking this substitution pattern were found to possess high DA autoreceptor selectivity. The observed dichotomy of DA agonists is discussed in relation to the possible involvement of multiple DA receptors and alpha-adrenoceptors.

The purported dopamine agonist DPI inhibits [3H]noradrenaline release from rat cortical slices but not [3H]dopamine and [14C]acetylcholine release from rat striatal slices in-vitro.

The effects of the purported dopamine (DA) receptor agonist (3,4-dihydroxyphenylimino)-2-imidazolidine (DPI) upon the in-vitro K+-induced release of [3H]DA and [14C]acetylcholine from rat neostriatal slices, and of [3H]noradrenaline from rat neocortical slices have been investigated and compared with those of the DA receptor agonist TL-99 and the alpha-adrenoceptor agonist clonidine, respectively. The rapid decomposition of the catechol compounds DPI and TL-99 in the Krebs-Ringer bicarbonate superfusion medium was shown to be inhibited by both the chelating agent EDTA and the reducing agent ascorbic acid. The results suggest that in-vitro DPI is unable to stimulate striatal DA receptors, whereas it is effective in stimulating cortical alpha 2-adrenoceptors (EC50 = 61 nM). It is concluded that DPI should be considered as a mixed alpha 1/alpha 2-adrenoceptor agonist and that the designation of DPI as a DA receptor agonist should be abandoned.

3,4-disubstituted phenyliminoimidazolidines as potential prodrugs of the purported dopamine agonist 3,4-dihydroxyphenylimino-2-imidazolidine (DPI).

A series of ether derivatives of the purported dopamine agonist 3,4-dihydroxyphenylimino-2-imidazolidine (DPI) has been prepared as potential prodrugs of the parent compound due to its relatively poor penetration into the brain. Their effects on both dopamine and noradrenaline utilization in the rat brain have been investigated using the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine. Apart from the parent compound, DPI, the diphenylmethane ether analogue showed some dopaminergic activity.

trans-N-n-Propyl-7-hydroxy-octahydrobenzo(f)quinoline, a rigid 3-PPP analogue with greater potency but lack of selectivity for dopamine autoreceptors.

trans- and cis-7-hydroxy-octahydrobenzo(f)quinoline were synthesized as analogues of the selective dopamine autoreceptor agonist 3-PPP. The trans compound appeared more effective than 3-PPP in the dopamine autoreceptor test model, but it also exhibited postsynaptic dopamine receptor stimulating activity. The cis compound was inactive in both these test models. It is concluded that in the trans compound the dopamine autoreceptor stimulating potency of 3-PPP has been much enhanced at the cost of dopamine autoreceptor selectivity.

The purported dopamine agonist (3,4-dihydroxyphenylimino)-2-imidazolidine (DPI) acts as a nonselective alpha-adrenoceptor agonist in inducing hypertension, hypomotility and hypothermia in the rat.

Following peripheral administration the purported dopamine (DA) agonist (3,4-dihydroxyphenylimino)-2-imidazolidine (DPI) was shown to increase the diastolic blood pressure of pithed rats and to decrease rat motility and rectal temperature. Dose-effect relationships were established and half-maximal effective doses for the hypertensive and hypothermic response to DPI were calculated to be 4.4 nmol/kg i.v. and 2.0 mumol/kg i.p., respectively. Pretreatment with various antagonists revealed that both alpha 1- and alpha 2-adrenergic mechanisms were responsible for the DPI-induced hypertension, hypomotility and hypothermia, indicating that DPI acts as a non-selective alpha-adrenoceptor agonist. Qualitatively the DPI-induced effects were found to correlate well with those reported for its structural analogue clonidine, thus suggesting a similar mechanism of action for these agents. DA receptor antagonists appeared to lack inhibitory potency towards any of DPI-elicited responses. The results do not therefore support the designation of DPI as a DA receptor agonist.

Evidence that the purported dopaminergic agonist (3,4-dihydroxyphenylimino)-2-imidazolidine (DPI) may reduce rat striatal dopamine turnover by an alpha 2-adrenergic mechanism.

The potent alpha-adrenergic agonist DPI, which has also been claimed to be a selective dopaminergic agonist, was shown to reduce rat striatal dopamine (DA) synthesis, DA utilization and DA metabolism following intraperitoneal administration (25 mumol/kg). An analytical procedure for the determination of DPI was developed and its application showed that DPI did not penetrate into the brain in substantial amounts. The possibility of a direct stimulatory action upon striatal presynaptic DA receptors was excluded by the demonstration that DPI lacked effectiveness both in the gamma-butyrolactone model and following intrastriatal administration. The selective alpha-adrenergic agonists phenylephrine (alpha 1) and tramazoline (alpha 2) decreased and increased DA metabolism, respectively, the yohimbine-induced increase being antagonized by DPI. The carbon-bridge analogue (3,4-dihydroxybenzyl)-2-imidazoline (DHBI) had about the same activity as DPI, whereas the potential DPI metabolite (4-hydroxy-3-methoxyphenylimino)-2-imidazolidine (HMPI) was without effect upon striatal DA metabolism. The results are discussed in relation to the remarkable resemblance with the literature data concerning clonidine. It is concluded that the DPI-elicited attenuation of striatal DA turnover is, in all likelihood, the result of a stimulation of alpha 2-adrenoceptors possibly located within the central nervous system. The results cast some doubt on the designation of DPI as a selective DA-inhibitory receptor agonist.