Comparison of the efficacy and safety of amikacin once or twice-a-day in the treatment of severe gram-negative infections in the elderly.

The aim of this study was to compare the efficacy and safety of amikacin given either as single injection or as two injections within 12-h interval in the treatment of severe gram-negative infections in elderly patients. Thirty-nine non-selected consecutive patients of a general internal medicine facility were randomized to receive the same total daily dose of amikacin either as a single dose (19 patients) or divided into two doses injected at 12-h interval (20 patients). Amikacin was used alone or in combination with metronidazole, clindamycin, fosfomycin or a beta-lactam. Clinical and bacteriological responses were satisfactory and comparable in the two groups. There was no difference between the once/day and the twice-a-day groups with respect to drug dosage, duration of therapy and concomitant treatment. Only one patient (BID group) showed a rise of serum creatinine during the observation period. Amikacin alone or in combination can be regarded as an efficacious and safe antibiotic in the treatment of severe gram-negative infections in elderly patients, whether the daily dose is administered in a single infusion or in a BID interval.

Metabolism of almitrine in extensive and poor metabolisers of debrisoquine/sparteine.

1. Almitrine bismesylate displays wide inter-subject variation in peak plasma concentrations and can induce peripheral polyneuropathy. 2. The phenotyped volunteer panel approach was used to examine whether almitrine oxidation displayed a genetic polymorphism of the debrisoquine/sparteine type. 3. There was no difference between poor and extensive metabolisers of debrisoquine with respect to the pharmacokinetics and metabolism of almitrine.

Lack of cardiovascular side effects of the new tricyclic antidepressant tianeptine. A double-blind, placebo-controlled study in young healthy volunteers.

In a double-blind, placebo-controlled, crossover study, the effects of therapeutic doses of the new tricyclic antidepressant tianeptine on cardiovascular function were closely monitored in 21 healthy volunteers during a 2-week treatment period. Blood pressure measurements, ECG recording, 24-h Holter monitoring, and echocardiography were carried out at 1-week intervals. Isotopic ventriculography was measured twice under each treatment. Tianeptine did not produce orthostatic hypotension or increase heart rate. No ECG changes could be observed and the cardiac conduction time remained unchanged. One subject presented with an increase in frequency of ventricular premature beats that could not be definitely attributed to the drug. Cardiac output assessed at rest and after a bicycle exercise stress test was not altered. The present study suggests that tianeptine is a tricyclic antidepressant endowed with less cardiac toxicity than classical tricyclic antidepressants.

Interaction between nonsteroidal anti-inflammatory drugs and loop diuretics: modulation by sodium balance.

Nonsteroidal anti-inflammatory drugs have been shown to decrease the natriuretic response to loop diuretics in many but not all studies. Recently, indomethacin was shown not to affect the natriuretic response to the new loop diuretic torasemide in healthy volunteers. Inasmuch as sodium balance has been reported to modify the effect of indomethacin on furosemide-induced natriuresis in dogs, we investigated the effect of indomethacin, under two sodium balances (50 and 150 mEq/day), on the natriuretic response to two doses of torasemide in six healthy volunteers. Under the low sodium diet, indomethacin reduced the natriuretic response to torasemide like that to furosemide. In contrast, on the normal sodium diet, indomethacin failed to affect the natriuretic response to torasemide. Indomethacin reduced base-line and diuretic-induced increase in plasma renin activity, plasma angiotensin II levels and urinary excretion of prostaglandin 6-keto F1 alpha to a similar extent under the two sodium diets. Our data show that indomethacin reduces the natriuretic response to torasemide in humans. Dietary sodium restriction is a significant determinant of the interaction between nonsteroidal anti-inflammatory drugs and loop diuretics in healthy volunteers, presumably because it allows loop diuretics to provoke an increase in renal blood flow which participates in their natriuretic action and is blocked by nonsteroidal anti-inflammatory drugs.

Study of the bioequivalence of three oral formulations of ibopamine in healthy volunteers.

Ibopamine (SK & F 100168-A), a new chemical entity, is capable of eliciting positive inotropic effects accompanied by vasodilating, diuretic and saliuretic activity after oral administration. The relative bioavailability and bioequivalence of 3 oral presentations of Ibopamine was examined after a single oral dose. Thirty healthy subjects (15 males and 15 females) received the 3 formulations at one-week intervals according to "single-blind assayer" latin-square crossover design. Two tablets of 100 mg ibopamine (SIMES formulations), 2 tablets of 100 mg ibopamine (UK formulation) and 1 tablet of 200 mg ibopamine (US-Tiltab formulation) were used. In a 4th occasion, all volunteers received again the 200 mg-tablet of the US-Tiltab formulation in order to assess the intra-individual variability of its oral bioavailability. Free epinine plasma levels were measured before and 10, 20, 30, 45, 60, 90, 105 min and 2, 2.5, 3, 4, 6, 8 and 24 h after each oral administration. Free epinine was assayed by HPLC/electrochemical detection method. The amount of drug absorbed as measured by the area under the curve, AUC0-8 h, and the rate of absorption, as measured by Cmax and tmax, were compared by examining the symmetric 95% confidence intervals. If the symmetric 95% confidence interval with respect to AUC is between 80% and 120%, two formulations are considered bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)

A brief, versatile, computerized, stress-inducing task derived from the Stroop color word test.

A brief, computerized version of the Stroop color word test (SCWT), which consists in reading words while ignoring their colors (reading task), is presented. It transitorily induced a moderate stress in non-anxious normal males, which was quantified with performance scores, subjective reports, urinary levels of catecholamines and vital parameters. Among the latter, cardiac frequency proved to be the most discriminant, enabling to distinguish between the different physical and mental loads imposed by the task. Stress was elicited rapidly (total task duration: 6 min) thanks to: 1) the presence of a conditioning series prior to the conflictual series, 2) a reconversion of the (usually voiced) semantic response into a color patch followed by a motor response, and 3) the use of conflicting acoustic signals as distractors. The brevity of the task reduced the 'spill-over' effect and prevented rapid habituation during repeated exposures. Both this feature and computerization, which allows great versatility in selection of the test parameters and in data handling, make possible the inclusion of this SCWT version in a clinical psychopharmacology psychometrical battery.

The pharmacokinetics of oxybutynin in man.

We have studied the pharmacokinetics of oxybutynin (Ditropan) after single oral (5 mg) and intravenous administration (1 and 5 mg), and after repeated oral administration in healthy volunteers. Oxybutynin was rapidly absorbed, maximum plasma concentrations (8 ng.ml-1) being reached in less than 1 h. The absolute systemic availability averaged 6% and the tablet and solution forms displayed similar relative systemic availability. Plasma concentrations of oxybutynin fell biexponentially, the elimination half-life being about 2 h. There was a large interindividual variation in oxybutynin plasma concentrations. Almost no intact drug could be recovered in the urine. During repeated oral administration steady-state was reached after eight days of treatment. The low absolute systemic availability of oxybutynin, the large interindividual variability in its plasma concentrations, and the apparent absence of intact oxybutynin in the urine suggest that its major pathway of elimination is hepatic metabolism.

Aztreonam in the treatment of serious gram-negative infections in the elderly.

The efficacy and safety of aztreonam in the treatment of serious gam-negative infections were investigated in 20 patients, 19 of whom were more than 60 years old. There were 13 cases of upper urinary tract infection, 6 of septicemia and one of peritonitis. Half the patients were in a critical clinical condition with significant severe underlying disease. Aztreonam was given i.v. or i.m. in doses ranging from 1.5 to 4 g/day according to the severity of the infection. The duration of treatment ranged from 7 to 20 days. In 5 patients with mixed infections due to gram-positive and anaerobic organisms in addition to gram-negative pathogens, aztreonam was given in combination with clindamycin and metronidazole as appropriate. Clinical and bacteriological cures were observed in all 20 patients. There were two cases of reinfection and 3 of superinfection--all occurred in patients with severe underlying disease. Untoward effects were few and of minor severity. Creatinine clearance remained stable or improved during aztreonam treatment, even in patients with significant renal impairment. In conclusion, aztreonam was shown to be both effective and safe in the treatment of serious gram-negative infections in elderly patients--even those with impaired renal function. In such indications aztreonam appears to be a good alternative to potentially toxic drugs such as the aminoglycosides.

Comparative pharmacodynamics of torasemide and furosemide in patients with oedema.

The pharmacodynamics of torasemide (1-isopropyl-3- ([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea), a new potent loop diuretic, were compared to those of furosemide in a double-blind controlled study in 18 patients with oedema of various origin. Torasemide behaved like furosemide in exerting a potent diuretic effect which culminated during the first 4 h after its administration. Nevertheless, torasemide was about 8 times more potent, exerted a longer lasting diuretic effect and was more potassium sparing than furosemide. Torasemide did not accumulate during repeated administration (5 days). It was well tolerated and efficient in the treatment of oedema due to congestive heart failure and hepatic cirrhosis. The long duration of action and the potassium sparing effect of torasemide compared to furosemide are promising features of this new potent loop diuretic.

Diffusion of oral ofloxacin (HOE 280) into human prostatic tissue: assessment by an improved high-performance liquid chromatographic method.

11 patients with a prostatic adenoma received a single oral 200 mg dose of ofloxacin 2 h before transurethral resection of the prostate. During the operation, blood samples and prostatic tissue cuttings were collected simultaneously. Ofloxacin was assayed by an original HPLC method with UV detection. The mean concentration of the unchanged drug was 5.10 mg/kg wet tissue and 1.81 mg/l in prostatic tissue and plasma, respectively. The 3.17 prostate/plasma ratio reflected a good penetration of ofloxacin into the prostatic tissue.

Torasemide, a new potent diuretic. Double-blind comparison with furosemide.

The pharmacodynamic effects of torasemide, a new potent loop diuretic, were compared with those of furosemide in a double blind controlled study in 18 hypertensive patients with oedema of various origins. Given orally for 5 days, torasemide was clinically very effective and well tolerated. On a weight basis, the diuretic, natriuretic and chloruretic effects of torasemide were about 8-times greater than those of furosemide. However, the kaliuretic effect of torasemide was only 3-times greater than that of furosemide, suggesting that torasemide is more potassium sparing than furosemide. Torasemide displayed a rapid onset of action, similar to that of furosemide but had a longer diuretic effect without any rebound phenomenon. Torasemide and furosemide did not effect creatinine clearance or uric acid excretion. Both furosemide and torasemide lowered systolic blood pressure but the effect of torasemide was more marked than that of furosemide. In this group of aged and hypertensive patients with oedema, the pharmacokinetics of torasemide was comparable to that reported in young healthy volunteers, and were similar on the first and fifth days of treatment. The long duration of action and the potassium sparing effect of torasemide compared to furosemide are promising features of this new loop diuretic in the treatment of oedema and hypertension.

Failure of indomethacin to impair the diuretic and natriuretic effects of the loop diuretic torasemide in healthy volunteers.

The effects of torasemide, a new potent loop diuretic, on renin release, water and sodium excretion were investigated in young healthy volunteers before and after 3 days of treatment with indomethacin. Torasemide 20 mg i.v. induced a rapid and biphasic increase both in plasma renin activity and plasma angiotensin II levels, which was almost completely abolished by pretreatment with indomethacin. Torasemide also increased urine volume, sodium excretion and, during the first hour after dosing, the creatinine clearance. None of the latter effects was impaired by indomethacin pretreatment. It is concluded that, like other loop diuretics, torasemide stimulates renin release by increasing renal prostaglandin production. However, at variance with what is observed with other loop diuretics, the diuretic and natriuretic effects of torasemide as well as the change in creatinine clearance do not appear to be inhibited by indomethacin.

Effect of oxametacin on endogenous uric acid clearance rate in healthy volunteers.

Oxametacin, a new non steroidal anti-inflammatory compound, with analgesic, antipyretic and anti-inflammatory properties comparable to those of indomethacin, has been claimed to be effective in treatment of acute attacks of gout. The present study comprises an investigation in 8 healthy volunteers of the effect on the endogenous uric acid clearance rate, of oxametacin administered alone or in combination with the conventional hypouricaemic agents benzbromarone or allopurinol. Whether given alone or in combination with these drugs, oxametacin failed to alter the clearance rate of endogenous uric acid. In view of its good tolerance and its possible efficacy in treatment of acute attacks of gout, the present data help to validate use of oxametacin in acute gout.

Pharmacokinetic study of cefuroxime in the elderly.

1 The pharmacokinetics of cefuroxime have been investigated in 18 patients at least 70 years old. The drug was given either by continuous infusion (7 cases) or by multiple injections (11 cases) for 3 to 11 days (mean duration: 7 days). 2 The unchanged drug was assayed in blood plasma and in the urine by high performance liquid chromatography (h.p.l.c). 3 Cefuroxime was cleared, unchanged, almost exclusively by the kidneys, even when kidney function was impaired. Creatinine clearance ranged from 1.02 to 4.08 1/h (17 to 68 ml/min) in this group of patients and plasma clearance of cefuroxime varied from 1.02 to 8.16 1/h (17 to 136 ml/min) (r = 0.7 P less than 0.001 for linear correlation), but the apparent rate constant for nonrenal elimination remained quite small (average: 0.04 h-1) and independent of creatinine clearance (r = 0.06, n = 17). 4 Since creatinine clearance decreases sharply with age, it might be suggested that cefuroxime dosage be related to creatinine clearance in the elderly, even when no renal impairment is suspected.