Absence of metabolic effects of the topical carbonic anhydrase inhibitors MK-927 and sezolamide during two-week ocular administration to normal subjects.

Potential systemic effects of the racemic carbonic anhydrase inhibitor MK-927 and its S-enantiomer, sezolamide hydrochloride, after topical ocular administration were investigated in a double-masked, randomized, placebo-controlled study in 16 healthy volunteers. A controlled diet was started 4 days before initiation of treatment and continued throughout the study. For 14 days six volunteers received bilaterally one drop of 2% MK-927 (1.2 mg) q.i.d., six received one drop of 1.8% sezolamide (1.1 mg) q.i.d., and four received the common vehicle q.i.d. Blood and urine electrolytes and acid-base profiles were measured before and on days 1, 7, and 14 of treatment, and 24-hour urine samples were collected daily. All values were compared with those on the pretreatment day. Taking the circadian variations of the parameters into account, no significant treatment effect was observed in either the daily profiles or the 14-day cumulative sodium, potassium, and citrate excretions. Because the usual variability of the measured biologic parameters has been reduced markedly by the stringent requirements of this study, it can be concluded that the induction of clinically significant metabolic changes by topically administered MK-927 or sezolamide is unlikely.

Influence of food and antacid administration on fluoride bioavailability from enteric-coated sodium fluoride tablets.

The relative bioavailability of enteric-coated sodium fluoride (NaF) tablets (10 mg F-) has been assessed following administration with a standard calcium-rich breakfast or calcium-poor lunch, and 2 h before or simultaneously with antacid administration (2.4 g aluminum-magnesium hydroxide), versus intake on an empty stomach. Twelve volunteers were studied 3 times according to an open, three-way crossover design over a 24 h period at weekly intervals. Meals were found to decrease the peak serum concentration of NaF from 122 micrograms/L during fasting (after baseline subtraction) to 71 and 88 micrograms/L with breakfast and lunch respectively, and to slow its absorption rate with Tmax increasing from 3.3 to 7.3 and 11.2 hours, without altering its bioavailability. Antacid impaired the bioavailability of NaF by 80% when administered simultaneously, with AUC decreasing from 987 to 155 micrograms.h/L, but had no significant effect when taken 2 h before NaF. In conclusion, the enteric-coated NaF tablets used in this study can be administered with food or after a 2-hour delay following antacid administration, but should not be taken simultaneously with antacid.

[Dose-response curve and preliminary clinical study of a laxative, lactilol]. / Courbe dose-réponse et étude clinique préliminaire d'un laxatif, le lactitol.

15 women complaining of chronic constipation were included in a prospective open trial to determine the laxative action and minimal effective dose of lactitol. Through the administration of increasing doses, an ED50 of 0.25 g/kg/day, was established. During a 15-day treatment period at the minimal effective dose, all patients had reduced symptoms of constipation as compared with a previous 15-day control period. Side effects of minor intensity were frequently recorded (flatulence, rumblings, wind, and, less frequently, abdominal cramps or nausea). Thus, the use of lactitol for symptomatic treatment of constipation deserves further clinical studies to determine better its indications and benefit.

Tolerability and pharmacokinetics of L-648,051. A leukotriene D4-receptor antagonist, in healthy volunteers.

Two formulations of L-648,051 (L) were studied [intravenous (i.v.) and aerosol (A)] in two separate trials. Study I (i.v.) involved 4 normal male subjects in a single blind dose ranging study where good systemic tolerability and safety was shown. However, dose dependent local irritation at the injection site was observed at all dose levels (35, 52.5 and 70 mg/5 min infusion). L has a high systemic clearance rate (1.2 1/min), a small volume of distribution (4.41) and a short plasma half-life (2.4 min). Study II (A) involved 16 normal male volunteers who received incremental aerosolized doses of L from 0.1 to 1.6 mg in a double-blind, placebo controlled, dose ranging study. Complaints of mild local irritation or discomfort in the upper respiratory tract were the only significant findings. No dose relationship of these complaints could be shown. In conclusion, L is a safe and well tolerated drug when administered by aerosol. It causes dose related local, but not systemic, adverse experiences when administered i.v. In view of this tolerability and of its demonstrated activity against LTD4-challenge in animals, clinical efficacy studies with the aerosol formulation are warranted.

[Psychotropic agents in elderly persons]. / Médicaments psychotropes chez les personnes âgées.

The response to narcotics, sedatives, hypnotics, antidepressants and antipsychotic drugs is modified in elderly patients. The effects of these drugs are enhanced, and dosage reduction is required. This phenomenon is gradual and occurs before any sign of senile dementia. The choice of a drug within a therapeutic class may depend on the severity of adverse reactions, some of which are particularly disturbing in elderly patients.

Does renal failure induce a decrease in cyclosporine blood concentrations?

Blood Cys concentrations were monitored twice weekly by RIA in nine patients undergoing renal transplantation. The Cys dose was adapted to obtain blood values between 100-400ng/ml. A negative correlation was found between plasma creatinine and blood Cys, even in those patients in whom the oral dosage was not changed (r = 0.65, n = 23, p less than 0.001). In vitro studies showed no effect of uraemic blood on Cys measurement. It seems probable that uraemia induces changes in distribution volume and/or gastrointestinal absorption of the drug. Careful monitoring of Cys during uraemia is therefore warranted.

[Monitoring amiodarone]. / Monitoring de l'amiodarone.

Serum levels of amiodarone (A) and desethylamiodarone (D) were determined by HPLC in 34 adults receiving loading (2 g) or maintenance doses (200 mg daily) of amiodarone. Serum levels of A after i.v. loading doses were much higher (1.35 micrograms/ml) than after equivalent oral doses (0.51 microgram/ml), suggesting low bioavailability. During maintenance therapy, very low levels of A were measured during the first 3 months of treatment (0.31 microgram/ml), after which they tended to rise (0.53 microgram/ml), as did the ratio of D/A. Among 4 children under maintenance therapy, one had high serum levels of A (1.50 micrograms/ml) and D (2.50 micrograms/ml) and showed nervous and cutaneous signs of toxicity.

Effect of digoxin on the sensitivity to flickering light.

1 The sensitivity to flickering light at various light frequencies (DeLange curve) was determined in 20 controls and 45 patients receiving maintenance doses of digoxin. 2 Flicker thresholds (mean percentage of maximal light modulation +/- s.d.; F 30 Hz) were 7.6 +/- 1.7 in controls and 9.4 +/- 1.7 in patients with optimal plasma digoxin levels (0.5-1.9 ng/ml), but they rose to 15.5 +/- 1.9 at subtoxic levels (2.0-3.0 ng/ml), and to 21.8 +/- 2.6 at toxic levels (above 3.0 ng/ml). 3 Flicker sensitivity was inversely correlated with plasma digoxin levels and returned to baseline values when the administration of digoxin was interrupted. 4 The DeLange curve seems to be a valuable tool to measure the toxic effects of digitalis on the visual system.

[Comparative study of a new package insert for benzodiazepines adapted for patients]. / Etude comparative d'une nouvelle notice d'emballage pour benzodiazépines adaptée aux malades.

A standardized, patient-oriented package insert for benzodiazepines has been compared with four package inserts printed by manufacturers for these drugs. The leaflets were submitted to 222 hospitalized patients randomly allocated to two groups; 108 received a manufacturer's notice and 114 the standardized notice. The patients were interviewed two or three days later and found the standardized notice more comprehensible than those of the manufacturers. Two independent experts assessed the adequacy of the notices and also found the standardized notice more appropriate for patients. The patients answered a questionnaire about the effects of the drugs and the precautions while using them. Those who had read the standardized notice were significantly better informed than those who had read manufacturers' notices. However, the level of understanding varied largely from one item to another, and depended on the level of education and age.

Enalapril maleate and a lysine analogue (MK-521): disposition in man.

1 The disposition of two angiotensin converting-enzyme inhibitor drugs was studied in normal volunteers. One drug was enalapril maleate (MK-421), which requires in vivo esterolysis to yield active inhibitor (MK-422). The other was a lysine analogue of MK-422 (MK-521), which requires no bioactivation. 2 Absorption of enalapril maleate (10 mg, p.o.) was rapid, with peak serum concentrations of enalapril observed 0.5-1.5 h after administration. Based upon urinary recovery of total drug (enalapril plus MK-422), absorption was at least 61%. Bioactivation appeared to be largely post-absorptive. From the ratio of MK-422 to total drug in urine, the minimum extent of bioactivation was estimated at 0.7. 3 A similar dose of MK-521 was absorbed more slowly, reaching peak serum concentrations 6-8 h following drug administration. Minimum absorption, based upon urinary recovery, was 29%. 4 Serum concentration v time profiles for both drugs were polyphasic and exhibited prolonged terminal phases. 5 Recovery in urine and faeces of administered enalapril maleate (intact and as MK-422) was 94%. Recovery of MK-521 was 97%. These results indicate lack of significant metabolism of these agents, apart from the bioactivation of enalapril.