Early phase II clinical trial of remoxipride in treatment of schizophrenia with measurements of prolactin and neuroleptic activity

Twenty hospitalized schizophrenic patients on haloperidol (doses 6 to 80 mg/day; median, 30 mg/day) underwent 4 days of placebo washout before being treated for 6 weeks with remoxipride, a new benzamide derivative with selective D2-dopamine receptor blocking properties. All patients completed the clinical trial period with week 6 doses ranging from 75 to 500 mg/day (median, 225 mg/day). Comparison of final scores with end of placebo washout showed improvement in schizophrenic symptoms in 10 patients and a reduction in the mean score for Clinical Global Impression of severity of illness (14.1%) and Brief Psychiatric Rating Scale total score (23.0%). Remoxipride caused less parkinsonism than the prior neuroleptic therapy and appeared to have little masking effect on tardive dyskinesia. Only slight evidence of serum neuroleptic activity was shown by radio-receptor assay measurements using [3H]spiperone binding and calf caudates, and the drug's effect on prolactin elevation was short-lasting (less than 10 hours). The mean elimination half-life of remoxipride was 5.9 hours. These results add to the consistent impression that D2 receptor blockade predicts clinical antipsychotic effects.     

Once-daily controlled release remoxipride is equieffective with twice-daily immediate release remoxipride in the treatment of schizophrenia

A controlled release (CR) formulation of remoxipride (Roxiam(?), Astra) given once-daily was compared to immediate release (IR) remoxipride given twice-daily, with respect to efficacy and tolerability, in a 4-week multicentre parallel-group dose titration (200-600 mg/day) study with acutely ill schizophrenic patients. Forty- three patients received remoxipride CR (mean dose 344 mg/day) and 49 patients received remoxipride IR (mean dose 346 mg/day). Efficacy was assessed using the Kolakowska version of the Brief Psychiatric Rating Scale (BPRS score of ≥ 18 points at entry) and the Clinical Global Impression scale (CGI), while extrapyramidal symptoms were rated using the Simpson and Angus scale. Both formulations of remoxipride produced clinical improvement, with the BPRS median total score falling from 35 at baseline to 16 at last rating in the remoxipride CR group, and from 33 to 12.5 in the remoxipride IR group. More than 70% of the patients in both groups were assessed as 'much improved' or 'very much improved' according to the CGI scale. Both formulations of remoxipride were well-tolerated, with a low incidence of treatment-emergent adverse symptoms, including extrapyramidal side effects. No statistically significant differences were detected between the treatment groups with regard to efficacy, safety or tolerability.     

Interaction study between remoxipride and biperiden

Twelve healthy male volunteers took part in a double-blind randomised cross-over study composed of three treatment sessions: remoxipride 100 mg; remoxipride 100 mg plus biperiden 4 mg; and biperiden 4 mg. Plasma and urine concentrations of remoxipride and biperiden, plasma prolactin levels, salivary flow and adverse events were recorded to assess pharmacodynamic interactions. Remoxipride and biperiden had no effect on each other's plasma concentrations. Biperiden did not affect the urinary recovery or renal clearance of remoxipride. Prolactin levels were unaffected by biperiden but increased following remoxipride administration. Differences in prolactin C_max and t_max following remoxipride versus concomitant (remoxipride + biperiden) treatment were not statistically significant. However, a slight but statistically significant (P=0.04) increase in prolactin AUC was observed after concomitant treatment. No significant differences could be observed between the recorded salivary flow in all the treatment sessions. Single doses of remoxipride and biperiden showed no pharmacokinetic or pharmacodynamic interaction.     

Pharmacokinetics and effects on prolactin of remoxipride in patients with tardive dyskinesia

The pharmacokinetics of remoxipride, a new selective dopamine-D₂ receptor antagonist with antipsychotic action, was evaluated in eight elderly psychiatric patients with tardive dyskinesia (TD). The daily oral doses of remoxipride were gradually increased from 50 mg per day to 200 mg t.i.d. over 2 weeks. The pharmacokinetics following the initial 50 mg dose (day 1) and the last 200 mg dose (day 15) of the drug were compared in serial samples. Plasma prolactin concentrations were assessed at the same time points. The area under the total plasma concentration versus time curves (AUC) of remoxipride increased proportionally with dose from day 1 to 15. The mean dose corrected AUC values for the total concentrations were 96.8 at day 1 (4×24.2, 50 mg single oral dose) and 92.2 µmol·h/l at day 15 (200 mg). The unbound fraction of remoxipride calculated on AUC was slightly higher on day 15 (20%) than on day 1 (15%) (P<0.05), indicating slightly concentration-dependent protein binding of the drug. The mean elimination half-life of total remoxipride was slightly longer on day 15 than day 1 (7.5 versus 5.3 h,P<0.01) The corresponding half-lives for the unbound concentrations were 6.4 and 3.9 h, respectively (P<0.01). The pharmacokinetics of remoxipride is similar in these TD patients and in non-TD patients in previous studies. Following repeated administration of remoxipride, tolerance to the prolactin-releasing action of remoxipride is observed. In plots of the relationship between the concentration of remoxipride and the prolactin increase during a dosage interval, the curve on day 15 was positioned markedly to the right of that on day 1. This indicates a decreased sensitivity to the prolactin releasing action of remoxipride following continuous treatment.     

Remoxipride: pharmacokinetics and effect on plasma prolactin.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in 15 healthy subjects after an intravenous infusion of 50 mg, an intramuscular injection of 100 mg and after administration of two immediate release capsules (A and B), each of 100 mg, in a cross-over study. The effect of the different remoxipride formulations on plasma prolactin concentrations was also studied. 2. The volume of distribution of remoxipride was 0.65 +/- 0.11 kg-1 (mean +/- s.d.). Total plasma clearance was 119 +/- 39 ml min-1, of which 31 +/- 13 ml min-1 was due to renal clearance. The absolute bioavailability after the i.m. and oral formulations was greater than 90%, indicating a small extent of first-pass metabolism. The mean elimination half-life was 4.8 +/- 1.4 h. The unbound fraction of remoxipride and the blood/plasma ratio were 0.19 +/- 0.03 and 0.64 +/- 0.06, respectively. 3. The transient increase in plasma prolactin was similar after all four remoxipride administrations and independent of the given dose.     

Influence of the dosing interval on prolactin release after remoxipride.

1. The prolactin response following administration of the D2-dopamine receptor antagonist remoxipride was studied in eight healthy male volunteers. The purpose of the study was to investigate the duration of a refractory period of prolactin release following two doses of remoxipride. A further aim was to compare the prolactin response following remoxipride and thyrotropin release hormone (TRH) during the refractory period. The subjects received two 30 min intravenous (i.v.) infusions of remoxipride 50 mg with different time intervals between the two doses, in a randomized six period crossover design. The time intervals between the two remoxipride doses were 2, 8, 12, 24 and 48 h. On one occasion the remoxipride dose was followed by an i.v. injection of TRH after 2 h. 2. The plasma peak prolactin concentrations obtained after the first remoxipride dose correspond to a maximal release of prolactin according to earlier studies. A small second peak of prolactin was observed after 2 h. The release was gradually increased with longer time intervals between the consecutive doses. The refractory period for a second prolactin release similar to the first one after remoxipride was found to be 24 h for most of the subjects. 3. TRH resulted in a faster and higher increase in prolactin response of a shorter duration than after remoxipride administered 2 h after the first dose.     

Steady-state pharmacokinetics of controlled release and immediate release formulations of remoxipride in patients with chronic schizophrenia

Twenty-four stable, chronic schizophrenic inpatients were entered in a double-blind crossover study designed to compare single dose and steady state pharmacokinetic profiles of an immediate release formulation (IR) 200 mg BID and a controlled release formulation (CR) of remoxipride 400 mg once daily. The rate of absorption of remoxipride CR was significantly lower than the IR formulation andt _max was prolonged from 1.3 to 7.9 h after a single dose and from 2.2 to 6.0 h after repeated dosing. Although the single dose of remoxipride CR was twice as large as the single dose of the IR, theC _max was similar for both formulations after a single dose. However, theC _max at steady state was slightly lower for CR. There was significantly less fluctuation in plasma concentrations at steady state with the CR formulation, although the average plasma concentration of remoxipride IR and CR was similar. The mean relative bioavailability with regard to the amount of remoxipride absorbed after remoxipride CR 400 mg once daily compared to IR 200 mg BID was 97%. It was concluded that the CR formulation is suitable for a once-daily administration from a pharmacokinetic point of view.     

Remoxipride,a selective dopamine D2 receptor antagonist,in tardive dyskinesia

Remoxipride in a dose range of 150–600 mg/day was evaluated in a single-blind placebo controlled study in eight patients with persistent tardive dyskinesia (TD). Dyskinesia score was significantly reduced without an increase in parkinsonism. The maximum mean reduction in dyskinesia rating score was 44%. After withdrawal of remoxipride TD scores returned to baseline levels without rebound deterioration. A negative correlation between remoxipride concentrations and the dyskinesia scores were found. Adverse effects were few and mild and no clinically relevant changes were seen in clinical chemistry, haematology or cardiovascular assessments. It is concluded that remoxipride in the dose range used has anti-dyskinetic effects but does not induce parkinsonism. Offprint requests to: U. Andersson     

Neuroendocrine responses to single oral doses of remoxipride and sulpiride in healthy female and male volunteers

Six female and six male healthy volunteers received 100 mg remoxipride, 200 mg sulpiride and placebo as single oral doses in a double blind trial with a randomized crossover design. The main objective was to compare the effect of the two drugs on serum prolactin levels, but effects on other hormones were also investigated. Remoxipride and sulpiride increased the serum levels of prolactin to similar peak levels. This effect was larger in female than in male subjects. Sulpiride increased prolactin levels at much lower plasma concentrations than remoxipride, and sulpiride's effect on prolactin lasted for considerably longer than remoxipride's. No consistent effects on serum levels of LH, FSH, GH, oestradiol, progesterone, testosterone or cortisol could be detected after remoxipride and sulpiride compared to placebo. No drug-related effects on plasma homovanillic acid (HVA) were found.     

Antihypertensive effect of slow-release nicardipine. A placebo-controlled cross-over study

Summary The magnitude and duration of the anti-hypertensive effect of slow-release nicardipine (SR-Nicardipine) have been compared with placebo in 36 uncomplicated essential hypertensives (diastolic BP 95 to 115 mm Hg after 1-month placebo washout). According to a double-blind, randomized, cross-over design they received SR-Nicardipine 40 mg b.d. and placebo for 1 month.At the end of each treatment period, blood pressure and heart rate were measured 12 h after the evening dose and 1, 2, 3 and 4 h after the morning dose.SR-Nicardipine significantly reduced systolic (SBP) and diastolic (DBP) blood pressure at each time after dosing.The absolute decrements peaked 4 h after dosing (–18.3 and –11.7 mm Hg, respectively) and more than 90% of the peak effect persisted 12 h after dosing, both for SBP and DBP.The heart rate was slightly increased by SR-Nicardipine.Adverse effects monitored with a check-list occurred in 31% of patients during SR-Nicardipine treatment and in 28% on placebo.Thus, SR-Nicardipine 40 mg b.d. has a maintained and significant antihypertensive effect lasting up to 12 h in essential hypertension.     

A placebo controlled trial of remoxipride in the prevention of relapse in chronic schizophrenia

Sixty-two DSM III chronic schizophrenic inpatients were selected for a double-blind, placebo controlled, multi-centre, relapse prevention study of remoxipride, a selective dopamine (D₂)-receptor antagonist. After a 1 month placebo washout, 23 patients had relapsed and were withdrawn. Of the remaining patients 19 were randomised to remoxipride (150–300 mg daily) and 20 to placebo. Their median age was 58 years, 26 were male, and the median duration of illness was 33 years. After 24 weeks a further total of 8 remoxipride and 17 placebo patients had been withdrawn. Excluding three patients withdrawn for reasons other than relapse, the comparative relapse rates were 37% and 75%, respectively (P=0.015). Efficacy analyses using clinical global impression (P=0.04) and change in BPRS scores (P=0.016) were in favour of remoxipride. Extrapyramidal symptoms were minimal in both groups. Treatment emergent adverse events were similar in the two groups. Remoxipride is therefore of potential value as a safe drug which is both effective and well tolerated in the long term management of chronic schizophrenic patients.     

Effect of urinary pH on the plasma and urinary kinetics of remoxipride in man

Summary The influence of urinary pH on the plasma and urinary kinetics of remoxipride in man has been studied in an open crossover trial in ten healthy male volunteers. Ammonium chloride (urinary pH 5.2) and sodium hydrogen carbonate (urinary pH 7.8) were used as pretreatments on two occasions in randomized order. On each occasion remoxipride 50 mg solution was administered orally and plasma and urinary concentrations of the drug were determined by HPLC and plasma prolactin concentrations by RIA.Remoxipride was rapidly distributed in the body according to a one-compartment model. The mean plasma elimination half-life (t_1/2) was 3.6 h in the ammonium chloride experiment and 6.2 h in the sodium hydrogen carbonate experiment. The mean plasma clearance of remoxipride was 141 and 89.9 ml·min^–1 in the acidic and alkaline conditions, respectively, and the corresponding mean renal clearances were 58.5 ml·min^–1 and 11.7 ml·min^–1. The urinary excretion of remoxipride up to 72 h after drug administration was 43.1% and 12.3% following acidification and alkalinization, respectively. Remoxipride induced a similar rapid, transient elevation of plasma prolactin under both conditions.Thus, the urinary pH has a marked effect on the elimination kinetics of remoxipride. After an overdose, treatment with ammonium chloride might be valuable in hastening elimination of remoxipride from the body.     

Plasma concentrations of remoxipride and haloperidol in relation to prolactin and short-term therapeutic outcome in schizophrenic patients

Plasma concentrations of remoxipride and haloperidol as well as prolactin (PRL) were determined in 20 patients with acute symptoms of schizophrenia. Ten patients received remoxipride and ten patients haloperidol for a period of 6 weeks. A significant linear correlation was found between the plasma level of remoxipride and the dosage applied (P < 0.02) as well as between the corresponding haloperidol dosage and plasma concentration (P < 0.05). In both patient groups a significantly reduction in psychopathology was observed during the trial period (P < 0.001). In the haloperidol group this was associated with a clearcut elevation of plasma PRL, whereas in the remoxipride group after an initial rise for 4 weeks, the mean PRL level returned to baseline at the end of the study.     

Gastrointestinal microbleeding associated with the use of etodolac, ibuprofen, indomethacin, and naproxen in normal males

Etodolac, a nonsteroidal antiinflammatory and analgesic drug, was used in a randomized, parallel group, open-label design study, with stool analysis conducted in a blind fashion, to compare its effect in normal men in doses of 400 mg (N = 11) and 600 mg (N = 12) b.i.d. on gastrointestinal microbleeding with that of 600 mg ibuprofen, q.i.d. (N = 12), 50 mg indomethacin in the morning, 50 mg at noon, and 100 mg h.s. (N = 9), and 375 mg naproxen b.i.d. (N = 9). Etodolac was given at about 2 1/2 and 3 1/2 times the mean effective dose used for treating patients with rheumatoid arthritis. The other drugs were given at their manufacturers' maximum recommended doses. Lead-in placebo was given for one week, active drug for one week, and washout placebo for one week. Fecal blood loss was measured by the 51Cr-tagged red cell method, and was averaged over days 4-7 (baseline), 11-14 (treatment period), and 17-20 (washout). The mean increase in blood loss for the treatment period for the 400 mg etodolac b.i.d. group (0.13 ml) and 600 mg etodolac b.i.d. group (0.10 ml) was significantly less (P = 0.001) than the corresponding values for ibuprofen (1.14 ml), indomethacin (1.20 ml), and naproxen (0.87 ml). There was no tendency for greater blood loss at higher doses of etodolac. Etodolac at doses in excess of the mean effective dose in osteoarthritis and rheumatoid arthritis caused significantly less microbleeding in normal male volunteers during the seven-day treatment period than the other drugs tested, and not clinically more than that occurring during baseline placebo.     

Once daily amlodipine in the treatment of mild to moderate hypertension.

1. The antihypertensive efficacy of once-daily amlodipine was studied in a group of 30 patients with mild to moderate hypertension in a double-blind, placebo controlled parallel group study. The dose range of amlodipine was 2.5-10 mg daily titrated at 2 weekly intervals for a total treatment period of 8 weeks. 2. Amlodipine produced a significant reduction in blood pressure compared with placebo, the mean difference between baseline and 8 weeks (corrected for placebo effect) being 16/12 mm Hg supine, 14/4 mm Hg standing. 3. Blood pressure returned to baseline values during a terminal 4 week washout period on placebo. 4. There were no significant effects on heart rate. 5. Two patients experienced slight ankle oedema while receiving amlodipine 10 mg daily but the active drug was otherwise well tolerated. 6. Plasma concentration of amlodipine, sampled 24 h after the preceding dose, increased as the dose titration sequence was followed, averaging 2.5 ng ml-1 on 2.5 mg, 4.9 ng ml-1 on 5 mg and 10.5 ng ml-1 on 10 mg.     

Remoxipride — a new potential antipsychotic compound

The tolerability and pharmacokinetics of remoxipride were studied in 18 healthy normal male volunteers. Increasing oral doses of 0.5–100 mg were given to eight male volunteers in one study (study I). In addition, an intravenous (IV) infusion of 20 mg remoxipride and a 20 mg oral dose were given in an open crossover study to ten males (study II). Remoxipride was well tolerated with respect to cardiovascular effects, clinical chemistry, body temperature and adverse effects in all subjects. Following IV administration, remoxipride plasma concentrations declined exponentially in five subjects and biexponentially in the remaining five. The mean apparent volume of distribution was 0.5 1/kg (SD=0.10) and the mean half-life 4.1 h (range 2.6–6.6). The recovery of unchanged remoxipride in urine was 10–36%, and the mean renal clearance was 32 ml/min (SD=13). Remoxipride was a low clearance drug with a total plasma clearance of about 120 ml/min (SD=41). The mean oral bioavailability was 96%. There was a linear relationship between the peak plasma concentration as well as the area under the concentration versus time curve and the administered dose. A transient increase in plasma prolactin concentrations occurred but there were no effects on plasma growth hormone levels.     

Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers

OBJECTIVE: To study the pharmacokinetics and accumulation of deramciclane and its metabolite N-desmethylderamciclane after 60 mg twice daily doses for 4 weeks. METHODS: Sixteen healthy male subjects, age range of 20-29 years, participated in this randomized, double-blind, parallel-group, placebo-controlled study. Ten subjects first received a single 60 mg dose of deramciclane followed by 60 mg deramciclane b.i.d. between days 4 and 31. Six subjects received matching placebo in a similar manner. Pharmacokinetics of deramciclane and N-desmethylderamciclane were determined on days 1, 10, 17, 24 and 31. Plasma prolactin concentrations were measured before drug administration and 4 hours after on the same days. Safety was monitored using repeat laboratory determinations and ECG recordings. RESULTS: The mean (SD) AUC(0-infinity) of deramciclane was 1,251 (385) ng x h/ml after the first dose. The AUC(tau) calculated for the dosing interval was significantly higher at week 1 (p = 0.048) than the AUC(0-infinity) after the first dose but thereafter there was no further accumulation of deramciclane. The mean accumulation indices at weeks 1, 2, 3 and 4 varied between 2.3 and 2.7 with no tendency to increase over time. The mean apparent elimination half-life of deramciclane was 24.9 (3.5) hours after the first dose and 29.3 (9.3) hours after 4-week repeated dosing; this difference was not statistically significant. The accumulation index of N-desmethylderamciclane increased from week 1 to week 2 but remained stable thereafter. The treatment was well tolerated. Plasma prolactin levels were not influenced by deramciclane administration. CONCLUSIONS: Deramciclane administration, 60 mg twice daily for 4 weeks to healthy male volunteers, is well tolerated, and there is no evidence of continuous accumulation of the drug during maintenance treatment. Deramciclane at a dose of 60 mg b.i.d. does not antagonize dopamine receptors to a significant degree.     

Lack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopram

STUDY OBJECTIVE: To determine whether the pharmacokinetics of the antidepressant citalopram are affected by ketoconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4. DESIGN: Single-center, double-blind, randomized, three-way crossover trial. SETTING: Research facility. PARTICIPANTS: Eighteen healthy male and female volunteers. INTERVENTION: Subjects received three treatments with a 14-day washout period: single dose of ketoconazole 200 mg plus placebo, single dose of citalopram 40 mg plus placebo, and single dose of ketoconazole 200 mg plus single dose of citalopram 40 mg. MEASUREMENTS and MAIN RESULTS: Pharmacokinetic parameters were determined after each treatment. The pharmacokinetic profile of citalopram administered alone was essentially identical to that when administered with ketoconazole. Similarly, the pharmacokinetics of the metabolite desmethylcitalopram were unaltered by ketoconazole. CONCLUSION: No changes in pharmacokinetics of citalopram were observed after coadministration of ketoconazole, suggesting that ketoconazole and other CYP3A4 inhibitors may be administered safely with citalopram. Furthermore, no adjustment of citalopram dosage should be necessary in most patients who receive the drug in combination with a CYP3A4 inhibitor.     

Clinical utility of nifedipine and diltiazem plasma levels in patients with angina pectoris receiving monotherapy and combination treatment

The clinical utility of nifedipine and diltiazem blood levels in patients with angina pectoris receiving monotherapy (N = 14) and combination treatment (N = 9) were assessed in a placebo run-in, double blind, randomized, crossover study. Compared to placebo, diltiazem (mean daily dose 360 mg), nifedipine (mean daily dose 90 mg) and combination diltiazem-nifedipine therapy (mean daily dose 55 mg of nifedipine, 360 mg of diltiazem) were associated with reductions in weekly angina attacks and nitroglycerin consumption. Although both drugs used as monotherapy and in combination were also associated with significant increments in exercise tolerance and other improved angina parameters, these changes were not related to the plasma levels of either drug. Nifedipine plasma levels were measured by gas chromatography and diltiazem plasma levels measured by reverse high-pressure liquid chromatography from specimens obtained 2-5 hours after the last previous dose, after 1, 2 and 3 weeks of treatment, and during baseline placebo and placebo washout periods. With combination therapy, there was no effect on the diltiazem plasma level compared to monotherapy. The significant decrease in the nifedipine dose in patients on combination therapy did not significantly change nifedipine plasma levels. Determinations of plasma levels of diltiazem and nifedipine in the management of patients is of no value in the management of patients with angina pectoris except for monitoring treatment compliance and overdosage.     

An open study of remoxipride in the long-term treatment of schizophrenia-

An open non-comparative multicentre study was carried out to evaluate the safety and tolerability of remoxipride over a treatment period of 12 months. The efficacy of the drug in controlling psychotic symptoms was also monitored. Eighty-five men and women aged 18-69 who met the Research Diagnostic Criteria for schizophrenia were entered into the study and after withdrawal of previous antipsychotic medication, treated orally with remoxipride 75-300 mg b.i.d. The treatment was well tolerated and most of the adverse symptoms reported were reduced in incidence at the last rating compared to baseline. Sleep problems (insomnia and increased sleep) and increased thirst showed an increase in incidence during treatment. The incidence of extrapyramidal side effects was low and less than at baseline; there was no evidence that remoxipride produced an increase in abnormal involuntary movements, the median weight of the group did not alter and remoxipride produced no significant effect on cardiovascular, clinical chemistry and haematology variables. It appeared effective in controlling psychotic symptoms and produced some improvement on over one third of the patients despite the fact that the majority of patients entered were not in a productive phase of their illness. The results indicate that remoxipride will be well tolerated and effective when given for the maintenance treatment of schizophrenia.