Effects of risperidone on psychometric and cognitive functions in healthy elderly volunteers.

RATIONALE: Dementia includes not only cognitive deficit but may also include psychiatric and behavioral symptoms. These psychological symptoms of dementia require specific treatment without deleterious effects on cognitive functions. OBJECTIVE: The aim of the present study was to assess the effects of a single dose of risperidone (0.25 or 0.5 mg) on psychomotor performances and cognitive functions compared to a placebo and to a positive control, lorazepam 1 mg, in 12 healthy elderly subjects. METHODS: This study was a randomized, double-blind, four-way crossover clinical trial involving four 8-h long treatment periods. The pharmacodynamic assessment criteria included a battery of psychomotor tests, a subjective evaluation and an electroencephalogram. Safety was evaluated by clinical laboratory tests, electrocardiogram and recording of adverse events. Concentrations of risperidone, 9-hydroxy-risperidone and lorazepam were determined before and 2 h after dosing. RESULTS. Few significant effects were observed on psychomotor tests with risperidone at all dosages. Risperidone was devoid of any deleterious effects on speed of reaction, vigilance and sustained attention, working and long-term memory and increased cortical arousal. Risperidone demonstrated minor impairment on motor activity (decreased finger taping), postural stability, and information processing (impaired digit symbol substitution). Contentedness subjective evaluation was decreased with risperidone 0.5 mg, 6 h after dosing. No significant difference was observed on EEG frequencies and no sedative activity was detected with risperidone. At 2 h after dosing, risperidone plasma concentrations were 1.54+/-0.99 ng/ml and 2.80+/-1.41 ng/ml; 9-hydroxy-risperidone concentrations were 0.77+/-0.46 ng/ml and 1.54+/-0.85 ng/ml after intake of 0.25 mg and 0.5 mg doses, respectively. Well-known detrimental effects of lorazepam on psychomotor performances were observed and sedative effects were confirmed by the EEG findings. At 2 h following lorazepam 1 mg administration, plasma concentrations were 13.40+/-2.17 ng/ml. None of both compounds induced serious adverse events. CONCLUSION: The results of this clinical trial conducted on healthy subjects demonstrated that low doses of risperidone, but not low doses of lorazepam, did not disturb the cognitive functions in the elderly.

Effects of terbinafine on the pharmacokinetics of digoxin in healthy volunteers.

STUDY OBJECTIVE: To assess the potential effects of terbinafine, a new synthetic allylamine antifungal agent, on the pharmacokinetics of a single 0.75-mg oral dose of digoxin. DESIGN: Randomized, double-blind, placebo-controlled, crossover study consisting of two treatment periods. SUBJECTS: Sixteen healthy men and women volunteers. INTERVENTIONS: During treatment A, placebo was administered once/day for 12 days; during treatment B, terbinafine 250 mg was administered orally once/day for 12 days. The washout period between treatments was at least 2 weeks. A single 0.75-mg oral dose of digoxin was administered on day 8 of each period. Blood samples were collected after administration of digoxin to determine pharmacokinetics. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, terbinafine did not alter the time course of the digoxin serum levels. Although the time to maximum peak concentration with terbinafine was slightly reduced, the maximum concentration and area under the serum drug concentration-time curve from time zero to 120 hours were not significantly different with terbinafine than with placebo. No drug-related side effects were reported with either active treatment, and no clinically significant changes in vital signs, physical examination results, electrocardiograms, or clinical laboratory results were observed. CONCLUSIONS: No special dosage adjustments for digoxin appear to be necessary during concomitant therapy with terbinafine.

Cyclosporine and nonsteroidal antiinflammatory drugs: exploring potential drug interactions and their implications for the treatment of rheumatoid arthritis.

A series of clinical pharmacology studies was performed to screen for possible pharmacokinetic/dynamic contributions to drug interactions reported in rheumatoid arthritis patients receiving cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs). No clinically relevant pharmacokinetic changes in any of the drugs were noted when single-dose cyclosporine was coadministered during a steady-state regimen of aspirin, indomethacin, or piroxicam in healthy volunteers. Only with diclofenac was an interaction observed whereby the diclofenac area under the concentration-time curve was doubled in the presence of cyclosporine. Based on the outcomes of the screening studies, steady-state coadministration of both diclofenac and cyclosporine was assessed in rheumatoid arthritis patients, confirming the drug interaction of diclofenac with cyclosporine. Although the drug interaction was accompanied by a significant rise in serum creatinine, there was no apparent concentration-effect relationship, inasmuch as the increase in diclofenac exposure was not related to the magnitude of increase in serum creatinine. Based on the results of these five drug-drug interaction studies and the known biotransformation pathways of nonsteroidal antiinflammatory drugs, it is speculated that the pharmacokinetic interaction, which is unique to diclofenac, is caused by inhibition by cyclosporine of diclofenac's first-pass metabolism. Caution and appropriate clinical monitoring are recommended whenever cyclosporine and NSAIDs are coadministered; however, diclofenac in particular should be administered near the lower end of its therapeutic range when it is initially combined with cyclosporine in the treatment of rheumatoid arthritis.

Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans.

Effects of the novel competitive N-methyl-D-aspartate (NMDA)-receptor antagonist SDZ EAA 494 were investigated on memory and attention in humans. SDZ EAA 494 was administered either as single doses at a dose range of 1-50 mg, or as multiple doses over the course of 1 week at doses of 25 mg once or twice daily. Selected cognitive functions were assessed at baseline, 2 and 4 h after single dose administration, and at baseline, 2, 4 and 8 h on days 1 and 7 of multiple dose administration. The assessments included simple and complex reaction time tests to assess attention, and verbal, non-verbal and spatial memory tests with immediate and late recall. Verbal and non-verbal memory test performance was significantly impaired at a dose level of 50 mg after single administration, and of 25 mg twice daily after multiple administration, without concomitant significant impairment of reaction time. Spatial memory test performance was not significantly affected. The maximum effect occurred 2 h postmedication and was more pronounced after repeated administration. These results suggest that the inhibition of NMDA-receptors in humans may impair memory processes.

Efficient phosphate binding using a combination of gluconolactate and carbonate calcium salts.

Although renal-failure-related hyperphosphataemia can be corrected by various phosphate binders, there remains a need for safer and more efficient formulations to precipitate phosphate. This work describes both a theoretical approach and a phosphate precipitation test in order to design efficient binding calcium salts formulations. The results show that the combination of a soluble calcium salt (the gluconolactate) and a proton-consuming calcium salt (the carbonate) can precipitate phosphate effectively. Furthermore, the theoretical computations correlate well with the ability of the salt to bind phosphate in vitro.

Pharmacological bridge to cardiac transplantation: current limitations.

Addition of intravenous enoximone to sympathomimetic agents permits a rapid and drastic improvement in the clinical and hemodynamical condition of patients in cardiogenic shock referred for a mechanical bridge to transplantation. The present experience, based on the management of 52 patients, permits us to point out the current limitations of this pharmacological bridge: the rate of sudden death, the incompleteness of the physical rehabilitation of the patients, and the vanishing effect of intravenous enoximone.

Cost and cost effectiveness of the mechanical and pharmacologic bridge to transplantation.

A prospective study has been carried out to evaluate the cost and cost effectiveness of the mechanical bridge (MB) or pharmacologic bridge (PB) to transplantation (HTx) in patients referred in cardiogenic shock (CS), who are candidates for Htx unresponsive to sympathomimetics. Selection between MB and PB was based on immediate efficacy of i.v. enoximone (2 mg/kg/BW) therapy. From 1986 to 1989, 37 patients who should have been immediately treated by MB entered the protocol. Six were unresponsive and rapidly received a Jarvik heart or left ventricular bypass (MB). Thirty-one improved (PB), with the need for HTx reconfirmed in 22 and performed in 14. Survival of the entire group was 70% and 51% at 1 and 3 months, respectively. Cost per patient was $45,843 ranging from 38,326 in PB patients to $84,683 in MB patients. Cost per patient transplanted after PB was $50,745. Cost per survivor at 1 year was $210,000 for all, ranging from $254,000 in MB to $192,455 in PB. Cost per added day of survival was higher in MB (+ 228%) at 1 month compared to PB. The difference was reduced at 1 year.

[Intravenous enoximone versus conventional treatment in acute lung edema. Preliminary results of a randomized study]. / Enoximone administré par voie intraveineuse contre traitement conventionnel dans l'oedème aigu du poumon. Résultats préliminaires d'une étude randomisée.

The aim of this open study was to compare the efficacy of Enoximone and conventional treatment in 44 patients with acute pulmonary edema. At the time of this interim analysis, 22 patients had received Enoximone (1 mg/kg by rapid intravenous injection every 8 hours for 48 hours) and 22 were given conventional treatment (furosemide, nitrates, dopamine-dobutamine). The treatment schedules were randomised. Clinical data was obtained at 0, 1, 2, 24 and 48 hours and evaluated using the Killip-Kimball score, dyspnoea, pulmonary rales, the need for additional therapy and patient mortality. The patients in the two groups were comparable in all clinical features except the sex ratio. The improvement of all clinical criteria of evaluation seemed to be greater in the Enoximone group, except during the first hour of treatment (due to the action of diuretics). The overall outcome was better in the Enoximone group (17 favourable responses compared to 11 in the group receiving conventional treatment). Normalisation of haemodynamic parameters was observed only with Enoximone. In addition, it became necessary to administer Enoximone to 9 patients in the conventional treatment group. At these doses, Enoximone was at least as effective as conventional treatment of acute pulmonary edema. What is more, no secondary effects or tachyphylaxis were observed during the period of hospital treatment.

Effects of enoximone on quality of life.

To assess whether an inotropic agent may affect quality of life in severe heart failure, a double-blind, placebo-controlled crossover study was performed in 10 patients over three periods of 3 weeks, including an initial control period of 3 weeks and periods on placebo or enoximone, 150 mg t.d.s. Quality of life was assessed by a questionnaire following initial training of patients to evaluate their symptoms after certain stresses, by visual analogue scales of symptoms, and by objective assessments during graded exercise. Daily dyspnoea score decreased from 33.2 +/- 2 (placebo) to 27.7 +/- 4 (enoximone) (P less than 0.01) and daily fatigue score decreased from 14.8 +/- 2.5 (placebo) to 12.6 +/- 2 (enoximone) (P less than 0.05). There were also significant beneficial responses in the mean daily NYHA class and in the duration of a walking test. Self-assessed global quality of life score increased from 2.7 +/- 0.6 (placebo) to 3.6 +/- 0.8 (enoximone) (P less than 0.05). It was concluded that over periods of 3 weeks, enoximone significantly improved self-assessed quality of life.

Acute pulmonary oedema: preliminary results of a randomized trial of the intravenous phosphodiesterase inhibitor, enoximone, vs conventional therapy.

The purpose of this open study was to compare the effects of enoximone and conventional therapy in 44 patients with acute pulmonary oedema. In this preliminary report, 22 patients were randomly assigned to the enoximone group (1 mg/kg bolus, every 8 hours for 48 hours) and 22 patients to conventional therapy (frusemide, nitrates, dopamine-dobutamine). Patients were assessed clinically at 0, 1, 2, 24 and 48 hours by the change in their Killip-Kimball score, dyspnoea, pulmonary rales, blood pressure, diuresis, requirement for additional therapy and/or death. Patient characteristics were similar except for distribution of the sexes. Improvements of each clinical parameter seemed more marked in the enoximone group, except during the first hour (due to the diuretics). The general course of the disease was more favourable in the enoximone group (17 cases vs 11 in the conventional therapy group), in which enoximone used alone was sufficient to normalize the haemodynamic variables. On the other hand, in the conventional therapy group, it was necessary to institute enoximone therapy in 9 cases. With the dosage used, enoximone appeared to be at least as effective as conventional therapy in acute pulmonary oedema. Moreover, no side-effects or tachyphylaxis appeared during the hospital assessment.

Placebo-controlled trial of oral enoximone in end-stage congestive heart failure refractory to optimal treatment.

A double-blind, randomized, concurrent trial of enoximone vs placebo was undertaken to assess the efficacy and safety of enoximone, 100 mg t.d.s. added to optimal therapy in 30 patients (mean age, 66.4 +/- 14 years) with severe congestive heart failure. Before inclusion, all patients remained markedly symptomatic despite treatment with diuretics, digitalis, vasodilators and angiotensin converting enzyme inhibitors. Symptoms and quality of life were evaluated at inclusion, and at days 4 and 31; 24-hour electrocardiography and Doppler echocardiography were performed at inclusion and at day 31. Clinical and echocardiographic baseline characteristics were similar in the two groups. During the study, 10 patients dropped out: 3 in the enoximone group (1 death) and 7 in the placebo group (3 deaths). At day 4, symptoms were improved in 13 enoximone-treated patients and in 8 patients on placebo (P less than 0.05). At day 31, symptoms were still improving in 10 of 12 patients on enoximone and in 6 of 8 patients on placebo (NS). No serious clinical side-effects were reported, and no statistically significant difference in the frequency of premature ventricular contractions between the two groups was apparent on Holter monitoring. Peak acceleration of ascending aortic blood flow at entry was 17 +/- 6 m/second2 in the enoximone group and 18 +/- 5 m/second2 in the placebo group (NS). At day 31, the change in peak acceleration was +20% in the enoximone group vs -6% in the placebo group (P less than 0.05). Cardiac index increased by 18% in the enoximone group (from 2.17 +/- 0.7 litres/minute/m2 to 2.4 +/- 1.0 litres/minute/m2 (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological bridge to cardiac transplantation.

From September 1985 to August 1988, 32 patients were referred from various intensive care units throughout Paris for urgent cardiac transplantation or for a mechanical bridge to transplantation. At time of admission, under maximal sympathomimetic therapy, the cardiac index (CI) was 1.81 +/- 0.26 l/min per m2, the pulmonary capillary wedge pressure (PCWP 31 +/- 7 mmHg), systemic vascular resistances (SVR) 2053 +/- 469 dynes s cm-5. In 25, diuresis was less than 25 ml/h. Five were anuric. Prior to any final decision, a new inotropic agent, enoximone, was infused in addition to previous treatment as a 10 min bolus iv 1.5-2 mg/kg every 8 h. In 3, the situation further deteriorated, leading to a Jarvik 7-70 implantation within 12 h. In 29 however, within 3 h, the Cl increased to 2.69 +/- 0.56 as SVR dropped to 1410 +/- 453 and PCWP to 18 +/- 7. Diuresis increased to more than 100 ml/h in all. This permitted an indepth evaluation of the transplant candidates leading to contraindications to transplantation in 16. Nine patients could be weaned off iv enoximone. Four of these are still living (NYHA class III) with a follow up of 6-17 months. In 11, transplantation was performed within 2 days. Four died within a month, 2 with multiple organ failure. One patient died after 5 months. Six are back to normal life, NYHA class I (follow up 10 months-2.5 years). This protocol suggests that in patients with extreme heart failure, immediate survival may be increased by iv enoximone therapy, permitting a better selection of the recipients, more efficient pre-transplantation intensive care and consequently a decrease in the indications for a temporary mechanical bridge to a staged transplantation.

[Dose-response relation of intravenous enoximone in congestive cardiac insufficiency]. / Etude de la relation dose-réponse de l'énoximone intraveineux dans l'insuffisance cardiaque congestive.

Enoximone (MDL 17043) is a new generation inotropic drug which acts by inhibiting phosphodiesterase and is endowed with both inotropic and vasodilator properties. The purpose of this study, which involved 23 patients aged from 18 to 75 years in NYHA class III or IV and with evidence of severe haemodynamic disturbances (cardiac index below 2.5 1/mn/m2, pulmonary wedge pressure above 15 mmHg), was to evaluate the acute haemodynamic responses to doses of enoximone that ranged from 0.25 to 2.50 mg/kg administered by bolus intravenous injection. Heart failure was either of ischaemic origin (6 cases) or idiopathic (10 cases) or due to various causes (7 cases). Group A patients (n = 11) received the drug in low doses (less than or equal to 1 mg/kg) as opposed to group B patients (n = 12) who were given high doses (greater than 1 mg/kg). Results were evaluated from the amplitude and duration of the haemodynamic response at maximum effect time (30 min). The following parameters were measured: cardiac index, pulmonary wedge pressure, systemic vascular resistance, mean arterial pressure and heart rate. Cardiac index and pulmonary wedge pressure were significantly improved in both groups (P less than 0.005): cardiac index +39 p. 100 in group A, +55 p. 100 in group B; pulmonary wedge pressure -36 p. 100 in group A, -48 p. 100 in group B; systemic vascular resistance -46 p. 100 in group B. Heart rate and arterial pressure were not significantly altered. The duration of response was 1 to 3 hours in group A patients and 4 to 8 hours in group B patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of teicoplanin in children.

A single dose of 6 mg/kg teicoplanin was infused over 10 min in six children of mean age 7 years, and a single dose of 6 mg/kg was infused over 20 min in four neonates of mean age 8.5 days. Serum sampling was performed at 0 and 10 min and at 1, 4, 12 and 24 h and thereafter 24-hourly, up to ten days. Urine was collected for each 24 h throughout the study in children. Teicoplanin was assayed by high performance liquid chromatography. Tolerability of teicoplanin was excellent both in children and in neonates. For all the patients the serum concentrations of teicoplanin followed an open two-compartment model. Mean Cmax was 48.6 +/- 16.7 mg/l (10 min) in children, and 19.6 +/- 1.05 mg/l (20 min) in neonates, and mean t1/2 beta was 20.5 +/- 5.5 h and 30.3 +/- 6.3 h, respectively. On the basis of the results dosage recommendations for children and neonates are made.

HPLC quantitation of the six main components of teicoplanin in biological fluids.

Teicoplanin, a new glycopeptide antibiotic belonging to the same class as vancomycin, is a mixture of six main components, designated A3, A2-1, A2-2, A2-3, A2-4 and A2-5. An assay method by higher performance liquid chromatography (HPLC) has been devised to separate and monitor each of these components in blood and urine.

[Treatment of septicemias and skin infections in burn patient by teicoplanin. Study of its skin diffusion]. / Traitement des septicémies et infections cutanées chez le brûlé par la téicoplanine. Etude de sa diffusion cutanée.

In this study, teicoplanin was administered to burnt patients by IV and IM route in monotherapy or in association with other antibiotics. 12 cases of septicaemia and 8 severe cutaneous cocci Gram + infections were treated. Dosage varied from 5 mg/kg to 14 mg/kg. Clinical cure was observed in 89% of cases, and eradication of cocci Gram + in 83%. The MICs of Staphylococcus were between 0.25 micrograms/ml and 4 micrograms/ml, with a majority of methicillin-resistant Staphylococcus at 1. Average through serum concentrations were 7.4 micrograms/ml, and peak serum concentrations were 26 micrograms/ml (1 hour after injection). Tolerance was good in 19 of the 20 cases (95%). Skin levels of teicoplanin were found to be 1.6 times the through serum level. It was noted that in burnt patients whose UBS is superior to 100, the dose should be increased by about 50%.