[Enduring loneliness. An interview survey of aged widows]. / Vivre sa solitude. Une enquête par interviews auprès de veuves âgées.

Interviews with 32 widows have given a clearer picture of the different ways of adaptation to solitude. The following types are distinguished: 1. the tormented (6 cases), who are crushed by loneliness and depression, even though they have the support of friends and relations 2. the isolated (7 cases), who may go for several days without seeing anyone 3. the misanthropes (3 cases): 'The less I see of my friends, the better I feel' 4. those who have found the answer to the problem of solitude in outside activities and contacts (5 cases) 5. those who have found tranquility after a lifetime of struggle (4 cases) 6. those with a naturally harmonious temperament who have overcome solitude and demonstrate the way to face it with courage, good sense and optimism (7 cases). This attempt at typology, which describes six different ways of living with solitude, has made possible a better analysis of the problem, its causes and its effects. Though solitude is often considered a negative aspect of growing old, it can also be a source of happiness, even of fulfillment. The capacity to live alone is something that has to be learned.

Behavior of amikacin in renal parenchyma of normal rats and of rats with acute obstructive renal insufficiency.

Aminoglycosides show a remarkable tendency to accumulate and persist in the renal parenchyma. In order to study the kinetics of this phenomenon for amikacin, rats received 25 mg/kg of this antibiotic i. p. and were sacrificed in groups of 6 up to 15 days after the injection. At 6 h, while the other organs and the serum were almost completely freed of amikacin, concentrations in the renal cortex reached 156 +/- 21 micrograms/g, or 6 times the peak serum level (instead of 20 times the peak serum level for gentamicin or sisomicin, a difference which is reduced by the fact that amikacin is given in higher dosage). They then decreased very slowly, according to a half-life of 122 h. Although it decreases glomerular filtration, ligation of ureters 20 h before the injection quadrupled the concentration in the cortex. These data explain the characteristics of the nephrotoxicity of amikacin and the increased toxic risk in acute obstructive renal insufficiency.

Behaviour of doxycycline in the tissues.

Little is known about the behaviour of antibiotics in the tissues. To investigate this problem, rats were sacrificed in groups of six, 1, 2, 4, 6, 8, 12 and 18 h after an intraperitoneal injection of 10 mg doxycycline/kg body weight. The antibiotic levels were determined in the nine major organs and in the serum by a microbiological method. One hour after injection, the doxycycline concentrations in all the tissues were already higher than the serum concentrations. After 4 h, the concentration exceeded 2.5 mug/ml in the lungs, muscles, testes and heart, and were much greater in the excretory organs: 11.4 +/- 4.1 mug/ml in the liver, 10.2 +/- 1.6 in the renal medulla and 27.8 +/- 7.0 in the renal cortex. Throughout the experiment, the lung and muscle concentrations were about double the serum concentrations, and this occurred with great regularity. Doxycycline is thus capable of penetrating extremely rapidly and intensely into tissues, while still retaining a great degree of freedom of movement between plasma and tissues.

Pharmacokinetics of ampicillin, cephalothin and doxycycline in various tissues of the rat.

To study the behavior of antibiotics in the tissues, rats were sacrificed repeatedly in groups of six, after the injection of 25 mg/kg ampicillin, 100 mg/kg cephalothin or 10 mg/kg doxycycline. These antibiotics were bioassayed in ten different organs. Standards were established for each organ by using identical organs, thus avoiding errors caused by tissue binding or inhibition. Penetration into the tissue is very fast. Compared to serum levels, lung, muscle, heart, testicle and spleen, levels are higher for doycycline, lower for ampicillin and variable for cephalothin: for example, lung/serum ratio at 1 h is 2.2, 0.5 and 1.1, respectively; muscle/serum is 2.3, 0.2 and 0.18. The decrease in tissue levels parrallels that in the serum for doxycycline, but is slower for ampicillin. The hepatic penetration of cephalothin is less than that of doxycycline or ampicillin. Levels are higher in the renal cortex than in the medulla for doxycycline, lower for cephalothin, and similar for ampicillin. The data enabled calculation of tissular pharmacokinetics. They have practical implications in the selection of antibiotics.

[Pharmacokinetic perturbations in kidney failure. Anomalies of metabolites and tissue diffusion (author's transl)]. / Perturbations pharmacocinétiques dans l'insuffisance rénale. Anomalies des métobolites et de la diffusion dans les tissus.

Complex pharmacokinetic perturbations follow kidney failure. Delayed excretion affects not only the original substance but also metabolites, as illustrated by the behaviour of glipizide and glibenclamide. Moreover, abnormal absorption, distribution, and metabolism of these drugs also often occur and are particularily evident for some beta-blocking agents. Analysis of tissue pharmacokinetics shows that aminosides accumulate in the renal cortexand persist there for several months. This phenomenon is markedly enhanced in acute obstructive kidney failure and largely accounts for the nephrotoxicity of these drugs.

Persistence of sisomicin and gentamicin in renal cortex and medulla compared with other organs and serum of rats.

Aminoglycoside antibiotics seem to accumulate and persist in the kidney. For a better understanding of this problem, groups of six rats received a single 4 mg/kg i.p. injection of sisomicin and were sacrificed repeatedly from 30 min to 28 days later. Sisomicin concentrations (bioassay) decreased rapidly in the serum, lung and other tissues. There was only a trace at six hours. The situation was totally different for the kidney. Concentrations in the cortex increased up to six hours with a maximum of 99 mug/g, 11 times higher than the peak value in the serum then decreased very slowly to 56, 18, and 7 mug/g, 2, 14 and 28 days, respecitvely, after injection. The concentrations in the medulla were lower than in the cortex but also showed an accumulation and persistence. Similar results were observed with gentamicin. In another experiment, daily injections of sisomicin or gentamicin during seven days demonstrated that the concentrations of both antibiotics six hours after the last injection were nearly three times higher in the cortex and twice as high in the medulla than after a single injection. These data explain why the nephrotoxicity of sisomicin or gentamicin involves chiefly the cortex, increases with the length of the treatment and can persist for several weeks after the last injection. Therapeutic implications need further studies.

[Pharmacokinetic effect of various antibiotics in the tissues]. / Pharmacocinétique de divers antibiotiques dans les tissus

The tissular pharmacokinetics of antibiotics were studied by sacrificing rats in groups of 6 at various intervals after the injection of ampicillin, cephalothin, doxycycline, gentamicin and sisomicin. A microbiological method was used to determine levels in 10 organs. The antibiotic penetrated rapidly into all the tissues but with very different affinities depending on the organ involved. The concentration of doxycycline in the tissues was always higher than in the serum and this relationship was maintained throughout the investigation. This was not true of ampicillin which disappeared a little more slowly from the organs, particularly the renal medulla, than from the serum. The aminosides showed a marked accumulation and prolonged persistence in the renal cortex: 4 weeks after injection concentrations were found which were above the maximum levels in the serum. When daily injections of 4 mg/kg aminoside were given, concentrations above 350 mug/g were found after 7 days. These findings permit a better understanding of antibiotic effectiveness and toxicity.

[Effect of various types of liver diseases on the behavior of cefoperazone]. / Influence de divers types d'atteinte hépatique sur le comportement de la céfopérazone.

Cefoperazone is a third generation cephalosporin mainly excreted by the biliary route. Hepatic dysfunction may have a pronounced effect on its pharmacokinetic behaviour. Sixty liver patients (acute viral hepatitis, alcoholic fatty liver and liver cirrhosis), without overt renal disease, have been studied and compared to controls. In liver disease the total clearance of cefoperazone is markedly decreased by reduction of extrarenal clearance, which is variable for each type of liver injury. Renal clearance does not change or may even increase, when hypoalbuminemia is present and compensates the reduction in extrarenal clearance.

[Behavior of gentamicin in the kidney parenchyma. Studies on rats during and after treatment with therapeutic doses]. / Le comportement de la gentamicine dans le parenchyme rénal.

The injection in rats of 4 mg/kg gentamicin results in accumulation and continued presence of the antibiotic in the renal parenchyma compared with its rapid elimination from other tissues. With repeated injections at 24-hour intervals over a period of 3 weeks, gentamicin concentrations in the cortex reach 356 +/- 139 microgram/g after 1 week of treatment, i.e. levels 50 times higher than the maximum serum levels. They then stay at a saturation plateau before decreasing very slowly to levels of 50 microgram/g 2 weeks and 15 microgram/g 15 weeks after the last injection. The accumulation takes place mainly in the cells of the proximal convoluted tubule. In the medulla, gentamicin behaves similarly but the levels are lower. Weeks after the last injection, urine levels of gentamicin are still appreciable. In spite of this enormous accumulation, the treatment does not result in disturbance of renal function or striking morphological changes. These observations are based on dosages of gentamicin corresponding to those used clinically. Compared to earlier observations based on the supratherapeutic administration of the antibiotic, the present study provides a better understanding of the mechanisms involved in gentamicin nephrotoxicity.

Nephrotoxicity of gentamicin. Action on subcellular organelles and pharmacokinetics in the kidney.

Our findings on the renal pharmacokinetics of gentamicin explain why: (1) gentamicin concentrations in the kidney reach levels high enough to provoke injuries to the organelles; (2) the morphological manifestations of toxicity involve primarily the convoluted proximal tubule (which constitutes the largest part of the cortex), since antibiotic concentrations in this area are especially high; (3) nephrotoxicity is related to duration of treatment; (4) urine may contain small quantities of gentamicin up to 3 weeks after the end of therapy (14, 22, 30); (5) nephrotoxicity continues after discontinuance of the treatment, and (6) the hepatocytes, whose lysosomes are very sensitive to the action of gentamicin, show no obvious signs of toxicity, since the antibiotic never attains a high enough concentration in this organ.

[Pharmacokinetics of a new cephalosporin, cefoperazone]. / Pharmacocinétique d'une nouvelle céphalosporine, la céfopérazone.

Cefoperazone is a semi-synthetic cephalosporin for parenteral use with an extended antibacterial spectrum covering Pseudomonas aeruginosa, Enterobacter cloacae and Serratia marcescens. Its pharmacokinetic properties were studied in 8 healthy subjects after 2 intravenous infusions of 2 g of the drug at a 12-hour interval. The mean peak serum concentrations were 134 +/- 16 microgram/ml and 143 microgram/ml. Cefoperazone was shown to possess a long half-life for a cephalosporin (1.7 hours). In our concentration range the drug is 90% protein bound. The apparent volume of distribution was a mean 11.4 liters and the renal clearance 18 ml/min. The cumulative urinary excretion was small, viz. 23% in 12 hours, indicating that there should be no need to modify the dosage regimen in renal failure. Comparison of in vitro studies with the pharmacokinetic properties show that 2 g cefoperazone given intravenously twice a day should inhibit most sensitive bacteria.

The effects of biliary obstruction on excretion of cefoperazone in the rat.

A study has been carried out on the influence of biliary obstruction on the elimination of cefoperazone (CPZ), an antibiotic mainly excreted in the bile. Rats were submitted to ligature of the common bile duct, given CPZ 100 mg/kg i.m., and killed 1 to 72 h afterwards. At death, measurements were made of CPZ concentrations in the serum, liver, lung, striated muscle, kidney, urine, intestinal wall and intestinal contents. The results were compared with those found in intact and in sham operated rats. Biliary obstruction led to a prolongation of the time taken for CPZ to disappear from the serum and markedly changed the way in which the drug was excreted. The amount of the drug excreted in the urine was 88% in the presence of biliary obstruction compared with 6% in intact rats and 14% in sham operated rats. The amount of CPZ in the small intestine 1 h after injection was very high in sham operated rats but only minimal amounts were found at this time in the presence of biliary obstruction. However, from 6 h after the injection, large amounts of CPZ were found in the intestinal contents despite the presence of biliary obstruction. In conclusion, in the presence of biliary obstruction, CPZ is eliminated by a combination of urinary and intestinal (non-biliary) excretion.

[Pharmacokinetic study of a cephalosporin, cefoperazone, in liver failure]. / Etude pharmacocinétique d'une céphalosporine, la céfopérazone, dans l'insuffisance hépatique.

The pharmacokinetics of cefoperazone, a semi-synthetic cephalosporin for parenteral use with a spectrum covering P. aeruginosa, E. cloacae, indole-positive Proteus and S. Marcescens, was studied after a 2-h intravenous infusion of 2 g of the drug in 6 patients with moderate liver function impairment (viral hepatitis in 4 cases, alcoholic fatty liver and cirrhosis in 2 cases). At the end of the infusion, mean serum concentrations (determined by a bioassay) were 208 microgram/ml in the patients and 134 microgram/ml in healthy volunteers. The half-life was 4.3 h in patients and 1.6 h in healthy volunteers. Volume of distribution and renal clearance were similar in the two groups. Extrarenal clearance of cefoperazone was lower in the patients (7.3 ml/min) than in the control group (59.4 mg/min). Urinary excretion of biologically active drug was markedly increased in the patients (79% of the dose) compared with healthy volunteers (24%). This study provides evidence that liver function impairment increases with both the apparent half-life of elimination and the urinary excretion of the drug. The results raise the question of the desirability of cefoperazone dosage adjustment in patients with hepatic diseases.