Biomedical subjects

G Labrecque

Publications and source records attributed to G Labrecque.

At least 19 recordsLinked to original sources

PubMed1997

Time-restricted feeding schedules modify temporal variation of gentamicin experimental nephrotoxicity.

The effect of timing of gentamicin dosing relative to food access periods was evaluated in experimental animals. Female Sprague-Dawley rats were treated for 4 and 10 days with gentamicin (40 mg/kg of body weight/day) intraperitoneally at either 0700, 1300, 1900, or 0100 h according to three food presentation schedules: food was available from 0800 to 1600 h in the first group, from 1600 to 0000 h in the second group, and from 0000 to 0800 h in the last group. Animals were thus subjected to a restricted feeding period. Results indicate that time-restricted feeding schedules displace the peak and the trough of gentamicin-induced renal toxicity, as evaluated by changes in the inhibition of sphingomyelinase activity, cellular regeneration (incorporation of [3H]thymidine into DNA of renal cortex), and blood urea nitrogen and serum creatinine levels, as well as histopathological lesions observed after 10 days of treatment. In fact, the toxicity was minimal when gentamicin was injected during the feeding period, while the maximal toxicity was found when gentamicin was administered during the fasting period. It is concluded that the feeding period can modulate aminoglycoside nephrotoxicity. The time of dosing of gentamicin relative to the time of feeding seems to be a more important modulator of gentamicin nephrotoxicity than the light-dark cycle.

Analysis of Variance↗

PubMed1996

Nephrotoxicity of amphotericin B in rats: effects of the time of administration.

Amphotericin B is a potentially nephrotoxic agent used for the treatment of severe mycoses and numerous fungal infections. Temporal variation in the nephrotoxicity of amphotericin B was studied in rats maintained on a light-dark period of 14 hrs of light and 10 hrs of darkness (light on: 06h00). Subgroups of animals were treated with a single daily i.p. dose of either 5% dextrose or amphotericin B (10 mg/kg/day) given at either 07h00, 13h00, 19h00 or 01h00 for 4 and 10 days. On day 4, no significant difference was observed in any parameter studied. On day 10, the cellular regeneration ([3H]-thymidine incorporation into DNA of renal cortex)(p<0.01), BUN levels (p<0.05), serum creatinine (p<0.05), and accumulation of amphotericin B in the renal cortex (p<0.05) were significantly higher when animals were treated with similar subcellular localization of amphotericin B in the proximal tubular cells of the renal cortex. These results showed a temporal variation in the nephrotoxicity of amphotericin B (peak toxicity occurred at 07h00) which is different from that of other nephrotoxic antibiotics such as aminoglycosides.

Amphotericin B↗

PubMed1996

Effects of fasting on temporal variations in nephrotoxicity of gentamicin in rats.

Evidence for temporal variations in the nephrotoxicity of low doses of aminoglycosides were recently shown by using specific and sensitive parameters of renal toxicity. The aim of the present study was to evaluate the effect of a short period of fasting on the temporal variations in the renal toxicity of gentamicin. Twenty-eight normally fed (i.e., food and water were available ad libitum throughout the experiment) female Sprague-Dawley rats (weight, 175 to 220 g) and 28 fasted rats (i.e., only water was available during a 12-h fast before and a 24-h fast after gentamicin injection) were used. The animals were synchronized on a 14-h light, 10-h dark cycle (lights on at 0600 h) for 1 week before gentamicin administration. In July 1993, each group of animals was treated with a single intraperitoneal injection of saline (NaCl, 0.9%) or gentamicin (150 mg/kg of body weight) at either the peak (1400 h) or the trough (0200 h) of the previously determined toxicity. On day 1, the 24-h urinary excretion of beta-galactosidase, N-acetyl-beta-D-glucosaminidase, and gamma-glutamyltransferase was significantly higher in normally fed animals treated with gentamicin at 1400 h than in their time-matched controls and in normally fed animals treated at 0200 h (P < 0.01), which had normal levels of these enzymes. By contrast, the urinary excretion of these enzymes was significantly higher in both groups of gentamicin-treated, fasted rats than in their time-matched control groups (P < 0.01), reaching levels similar to those measured in normally fed rats treated at 1400 h. The accumulation of gentamicin was significantly lower in the renal cortex of normally fed rats treated at 0200 h than in rats treated at 1400 h (P < 0.05), but this time-dependent difference was not found in fasted rats treated at 0200 and 1400 h. Immunogold labeling done on ultrathin sections and observed by electron microscopy showed a similar subcellular localization of gentamicin in normally fed and fasted rats treated at either 1400 or 0200 h. These results suggest that the feeding period is of crucial importance in the temporal variations of the nephrotoxicity of gentamicin in rats.

Animals↗

PubMed1996

Temporal variation in nephrotoxicity of low doses of isepamicin in rats.

The temporal variation in the nephrotoxicity of low doses of isepamicin was studied in male Sprague-Dawley rats treated with a single daily intraperitoneal injection of saline (NaCl, 0.9%) or isepamicin (80 mg/kg of body weight) at either 0800, 1400, 2000, or 0200 h for 4 and 10 days. On day 10, the cellular regeneration (incorporation of [3H] thymidine into DNA of renal cortex) and cortical accumulation of isepamicin were significantly higher in animals treated at 1400 h than at 0200 h (P < 0.01). Immunogold labeling studies showed that isepamicin was essentially localized in the lysosomes of proximal tubular cells in all treated groups, but the density of the gold particles over the lysosomes was higher in animals treated at 1400 than at 0200 h. The results of the present study show that the renal toxicity of isepamicin was maximal at 1400 h (midlight period) and minimal at 0200 h (middark period).

Animals↗

PubMed1996

Day-night treatment difference of tobramycin serum and intrarenal drug distribution and nephrotoxicity in rats: effects of fasting.

The effects of short-term food deprivation on the serum and renal distribution and nephrotoxicity of tobramycin were studied in female Sprague-Dawley rats maintained on a 14-h light/10-h dark cycle (light on: 06:00). For the distribution study, a single injection of tobramycin (40 mg/kg, i.p.) was administered at 14:00 or 02:00 to normally fed animals or to animals fasted for 12 h before tobramycin injection; these treatment times correspond to the peak and trough of tobramycin nephrotoxicity as previously determined in other studies. The serum and cortical levels of tobramycin were significantly higher 60, 120, and 240 min after the injection in fasted animals treated at 02:00 compared with normally fed animals treated at the same time (p < 0.05). In animals injected at 14:00, similar levels of tobramycin were measured in both fasted and fed rats. In the nephrotoxicity study, female Sprague-Dawley rats were fasted for 12 h before and 24 h after the timed single injection of tobramycin (150 mg/kg, i.p.). The 24-h urinary excretion of beta-galactosidase was significantly higher in fasted animals treated at 02:00 than in fed rats treated at the same time of day. Seventy-two hours following tobramycin injection, serum creatinine levels and cortical levels of tobramycin were significantly higher in fasted rats treated at 14:00 than at 02:00 and in fed rats treated at 14:00. These data suggest that a short period of food deprivation modulates the temporal variations of tobramycin nephrotoxicity.

Animals↗

PubMed1996

[Biological rhythm, inflammation and non-steroidal anti-inflammatory agents].

The inflammation is characterized by a multifrequency time structure described both in the edematous reaction and in the migration of neutrophilic polymorphonuclear (PMN) in the inflammatory site. The circadian rhythm of PMN migration appears to be similar when the migration was induced by BCG, LPS or carrageenan. The corticosteroids play an important role in the mechanisms in the circadian rhythm of PMN, but recent data in intact and castrated mice indicated that testosterone is also involved in these mechanisms. In arthritic patients, the signs and symptoms of the diseases varied as a function of time of day and of the type of arthritic diseases. Human data with indomethacin, ketoprofen and piroxicam indicated that it is possible to find an optimal time of day for the administration of these non-steroidal anti-inflammatory agents (NSAID). Clinicians can use these chronopharmacological data to maximize the analgesic effect and to minimize the side effects of the NSAID. The research on biological rhythms in inflammation and in the effects of NSAID lead to a better understanding of the mechanisms of inflammation and to the rational use of the drugs in arthritic patients.

Animals↗

PubMed1995

Biological rhythms in the inflammatory response and in the effects of non-steroidal anti-inflammatory drugs.

It is well known that some signs and symptoms of rheumatoid arthritis (RA) vary within a day and between days, and the morning stiffness observed in RA patients has become one of the diagnostic criteria of the disease. Research carried out in the last 10 years confirmed these clinical observations, and circadian, circaseptan or circannual variations were detected in experimental inflammation and in patients with arthritis diseases. The human data showed also that large interindividual differences can be found in the symptoms of RA. The chronopharmacological studies carried out with the non-steroidal anti-inflammatory drugs (NSAID) revealed circadian and circannual variations in the effectiveness, toxicity and pharmacokinetics of NSAID. A review of the available data suggests that peak and trough values found in different arthritic diseases do not occur at the same hour of the day and that the side effects produced by NSAID are more important after the morning than the evening administration. This information should be used by clinicians to determine when to administer drugs to arthritic patients, to optimize the effectiveness of NSAID and/or to reduce the side effects of these drugs. These new data could also be useful to physicians who would like to individualize NSAID use in patients with different arthritic diseases.

Animals↗

PubMed1995

Biological rhythms in pain and in the effects of opioid analgesics.

Pain is difficult and sometimes frustrating to treat, even though new devices and new approaches have been developed in recent years. Pain varies tremendously from one patient to the next, and there are also some studies suggesting that the intensity of pain varies according to time of day. In animal experiments, a relationship between the reaction to pain and the rhythmicity of plasma endorphin concentrations was suggested because reactions to pain (such as jumping from a hot plate) were in phase with plasma endorphin levels: latencies were longest and plasma levels were highest during the resting period of rodents. In human studies, pain induced experimentally was reported to be maximal in the morning, or in the afternoon or at night. These divergent findings may be due to methodological differences, as pain was produced by different methods, many parameters were used to quantify pain intensity, and the psychological aspect of pain was rarely considered by authors. A circadian pattern of pain was found in patients suffering from pain produced by different diseases. For instance, highest toothache intensity occurred in the morning, while biliary colic, migraine, and intractable pain were highest at night. Patients with rheumatoid arthritis reported peak pain early in the morning, while those with osteoarthritis of the knee indicated that the maximal pain occurred at the end of the day. The effectiveness of opioids appears also to vary according to time of day, but large differences in the time of peak and low effects were found. Investigators found that peak pain intensity and narcotic demands occurred early in the morning, while others found maximal pain at the end of the day. Pain is a complex phenomenon and efforts should be made to standardize the methods used in studies and to describe accurately the diseases causing pain because the patterns of pain may be specific to each clinical situation. Further research should be aimed at characterizing the chronobiology of pain in different experimental and clinical situations and to determine when the analgesic drugs are producing maximal effectiveness. This information is needed before clinicians can be persuaded to use chronopharmacological data when they prescribe analgesic drugs to their patients.

Analgesics, Opioid↗

PubMed1995

Twenty-four hour pattern in symptom intensity of viral and allergic rhinitis: treatment implications.

The symptoms of rhinorrhea secondary to influenza and cold virus or seasonal and perennial allergic rhinitis are circadian rhythmic. Cough frequency and handkerchief use by persons suffering from virus-induced rhinorrhea are more prominent during the daytime, especially during the initial hours after awakening from nocturnal sleep. The elevation in sublingual temperature as well as the decrement in mental alertness associated with influenza in particular are more profound at this time. Sneezing, blocked nose, and runny nose secondary to allergic rhinitis are also greater in intensity during the morning in approximately 70% of sufferers. The day-night variation in symptom intensity amounts to approximately 20% of the 24-hour mean level. The treatment of these diseases and their symptoms has traditionally involved equal-interval, equal-dose (homeostatic) medication schedules. The effects of antihistamine and antiinflammatory medicines may be enhanced by timing them to the day-night temporal pattern in symptom manifestation and intensity to achieve an optimization of their beneficial effects with control of toxicity, that is, as a chronotherapy.

Anti-Inflammatory Agents↗

PubMed1995

[Is it still possible to reduce the incidence of nephrotoxicity of aminoglycosides?].

Aminoglycosides are still widely used alone or in combination with a beta-lactam antibiotic for the treatment of severe Gram negative infection. Oto- and nephrotoxicity are the major side effects associated with the use of these drugs. Although several risk factors associated with aminoglycoside nephrotoxicity have been identified, only few therapeutic approaches were suggested to reduce the incidence of their toxicity in patients. The single daily injection is the only approach actually used to reduce the renal toxicity of aminoglycosides in patients. However, the relationship between the nephrotoxicity of aminoglycosides and the time of the day these drugs should be given has never been explored in patients. Data obtained in laboratory animals indicated that temporal variations can be detected in the renal toxicity of aminoglycosides: the nephrotoxicity was observed during the rest period of the animals while no toxicity was found at other times of the day. Other studies suggested also that food intake can modulate the temporal variations in the nephrotoxicity of aminoglycosides. A better knowledge of the risk factors associated with the renal toxicity of aminoglycosides, a reduction in the number of daily injections of aminoglycosides, administration of aminoglycosides at the time of the lowest toxicity of the drug in patients submitted to an appropriate diet are the most interesting approaches to reduce the incidence of the renal toxicity of these agents.

Aminoglycosides↗

PubMed1994

Nephrotoxicity of low doses of tobramycin in rats: effect of the time of administration.

The circadian and the circannual variations of the nephrotoxicity of tobramycin were studied in female Sprague-Dawley rats. Animals were maintained on a light-dark period of 14/10 hrs (light on: 06h00 to 20h00). They were injected once daily for 4 and 10 days with saline or tobramycin at a dose of 40 mg/kg/day i.p. at either 08h00, 14h00, 20h00 and 02h00, in April 1991, July 91, October 91, January 92. In April 91, tobramycin injected at 14h00 during 10 days induced a significant increase of [3H]-thymidine incorporation into DNA of renal cortex as compared to other groups (p < 0.01): toxicity was highest at 14h00 and lowest at 02h00. No temporal change was observed in the renal cortical accumulation of tobramycin, and in serum creatinine after the 4 or 10 days of treatment. In experiments done in April, July and October 1991 and in January 1992, no circannual variation was found in tobramycin cortical levels but peaks of toxicity were observed at 02h00 in April and October 1991 and at 14h00 in July 1991 and January 1992. There was no linear correlation between the toxicity and the tobramycin accumulation in the renal cortex (r = 0.21). The data suggest that the circadian changes in tobramycin toxicity are due to temporal changes in the susceptibility of renal cells to tobramycin.

Animals↗

PubMed1994

Temporal changes of pharmacokinetics, nephrotoxicity, and subcellular distribution of tobramycin in rats.

The present study was designed to determine the temporal changes in tobramycin nephrotoxicity during the dark and the light periods of the day and to look for the mechanisms of such changes. Female Sprague-Dawley rats (9 to 11 weeks old) were housed in a 14-h-light-10-h-dark cycle (lights on 0600 to 2000 h). A bolus of tobramycin (60 mg/kg of body weight) was intravenously injected into a first group of 15 rats, at either 1400 or 0200 h. Six blood samples were taken from each rat, 30 to 210 min after the bolus injection. The total clearance of the drug was reduced during the rest period (1400 h) of rats compared with the activity period (0200 h) (P = 0.0007). Another group of 99 rats was given intraperitoneally a single dose of tobramycin (40 mg/kg), and renal cortices were collected 2 to 222 h after injection. The cortical drug levels were always higher in animals injected at 1400 h than in those injected at 0200 h. A last group of 32 rats was used in the studies of tobramycin (30 mg/kg/day, once daily for 10 days, intraperitoneally) nephrotoxicity and subcellular distribution. Weight gain in the rats receiving tobramycin (both 1400 and 0200 h) was significantly (P = 0.028) less than that in the controls. Nephrotoxicity, indicated by the incorporation of [3H]thymidine into cortical DNA and urinary excretion of N-acetyl-beta-D-glucosaminidase, was significantly higher in animals treated at 1400 h than in those treated at 0200 h. No difference in the subcellular distribution of tobramycin was observed. The data indicate that the reduction in the clearance of tobramycin during the rest period is in part responsible for the higher nephrotoxicity in rats.

Acetylglucosamine↗

PubMed1993

Chronopharmacology of albuterol in hospitalized asthmatic children.

Eleven children (8-16 years old) hospitalized for acute bronchospasm were included in this investigation. Throughout the study, the children received the standardized course of therapy for hospitalized asthmatics with corticosteroids and albuterol nebulizations. Children receiving ipratropium were excluded from the study. Spirometric measurements, including forced expiratory volume in 1 s (FEV1), were made immediately before and 30 min after each albuterol nebulization over a 24-h period. The well-known temporal changes in FEV1 were observed in patients suffering from nocturnal asthma (NA): basal values were maximal at midday (10 a.m. to 2 p.m.) and lowest in the evening or at night (10 p.m. to 6 a.m.). This 24-h variation in lung function was not found in children without nocturnal exacerbations of their asthma. A 24-h variation was also observed in albuterol-induced bronchodilation in patients with NA: maximal effectiveness occurred at night, and lower effect was obtained with the midday administration. The albuterol-induced increases in FEV1 were not clinically significant in children without nocturnal asthma except when the beta 2-agonist was inhaled between 10 p.m. and 2 a.m. The data suggest that patients with nonnocturnal asthma might have different drug requirements than those with nocturnal symptoms.

Adolescent↗

PubMed1992

Time and dose dependent effect of indomethacin on BCG induced PMN migration in mice.

The effect of three doses of indomethacin (Indo) on BCG-induced PMN migration at different times of day was studied in Swiss mice kept on a lighting regimen of LD 12:12, with L from 07:00 to 19:00. Experimental granulomas were induced by subcutaneous implantation of BCG-impregnated cell traps for a time span of 480 min. Doses of 1, 3 and 9 mg/kg of Indo were given orally one hour before trap implantation, at 01:00, 05:00, 09:00, 13:00, 17:00 and 21:00 hr. In sham animals, the maximal PMN count occurred at 17:00 hr. In treated mice, Indo increased or decreased the number of PMN/mm2 as a function of time of administration. Cell migration was inhibited at 17:00 hr by all 3 Indo doses, while the number of PMN in the cell trap increased at 21:00 hr. Various dose-effects were obtained at the other times of day. Several hypotheses are proposed to explain the conflicting data. The results indicate the importance of the time of drug administration in biology.

Administration, Oral↗

PubMed1991

Biological rhythms in the absorption, distribution, metabolism and excretion of drugs.

Studies carried out in the last 20 years indicated that biological rhythms can be detected in the pharmacokinetics of most classes of drugs. These time-dependent variations could be due to parallel changes in the physiological functions and variables involved in the absorption, distribution, metabolism and excretion of drugs. A review of the data available suggests that the peak and trough values of these functions and variables do not occur at the same hour of the day in every factor involved in drug disposition. This information could be used to predict the time-dependent changes in the pharmacokinetics. The presence of circadian variations in the kinetics of drugs raise the rather old question: "When to administer drug?"

Absorption↗

PubMed1991

Biological rhythms in the physiology and pharmacology of blood coagulation.

This article reviews the current knowledge on time-dependent variations in the physiology of blood coagulation and in the anticoagulant effect of heparin and warfarin. Animal data indicated that the shortest blood clotting time and the highest levels of coagulation factors II, VII, and IX were recorded during the resting period of the animal. These circadian rhythms were not altered by modifications of the lighting regimens. In healthy volunteers, the prothrombin time was longer at the end of the afternoon than early in the morning; the acrophases of activated partial thromboplastin time and thrombin time occurred in the evening or during the night. The acrophases of fibrinogen, factors II, VII, VIII, and a-1-antitrypsin were obtained in the morning. There is no agreement on the chronobiology of platelet aggregation, and differences can be found in the time of maximal aggregability. The chronopharmacological studies of heparin infused at a constant rate to patients with thromboembolic diseases suggested that maximal effectiveness occurred at 04:00, while it was minimal at 08:00. Animal data indicated that oral administration of warfarin at the end of the activity period of rats produced maximal inhibition of vitamin K-dependent factors. This was the time of day when warfarin interference with the vitamin K cycle of the liver was highest. Further studies are needed to determine the clinical significance of biological rhythms in the physiology and pharmacology of blood coagulation.

Animals↗

PubMed1990

Temporal variation in the effects of warfarin on the vitamin K cycle.

In this in vivo study, the time-dependent effect of oral sodium warfarin was studied in male rats synchronized under a 12-hr light-dark cycle (light 0600-1800). Groups of 5 animals received an oral dose of 500 micrograms/kg of warfarin or saline at 0600 or 1800 and 1 mg/kg of vitamin K 8 hr later and the rats were sacrificed 240 min after vitamin K administration. The activities of the vitamin K reductase and vitamin K epoxide reductase were measured indirectly by determining the content of vitamin K1 and vitamin K epoxide reductase in the plasma and liver. The data obtained in control rats indicated that vitamin K and vitamin K 2,3 epoxide concentrations in plasma and liver were higher (P less than 0.05) at 1800 than at 0600. Warfarin had a greater (P less than 0.05) inhibitory effect on the vitamin K and vitamin K-epoxide reductases at 0600 compared to 1800; plasma levels of S- and R-warfarin did not vary with time of administration. The findings suggest that the activity of both reductases under control conditions, and the warfarin-induced inhibition of these enzymes varied depending on the time of drug administration.

Administration, Oral↗

PubMed1989

Circadian rhythms of blood clotting time and coagulation factors II, VII, IX and X in rats.

The 24-hr variations in clotting times and vitamin K-dependent blood coagulation factors were studied in rats kept on a 12-hr light-dark cycle (light on: 0600-1800 hours). Clotting times were determined under a binocular microscope by measuring the time required for the formation of the first fibrin thread. Factors II, VII and X were analyzed by the prothrombin test while the factor IX was quantified using the activated partial thromboplastin time assay. Results indicated that the clotting times were significantly longer during the dark (activity) period with a peak at 1:00 and a trough at 17:00. Similarly, a variation was found in factor activity levels: prothrombin (II), factor VII and factor X had higher activities during the light span (rest period). The highest activities found at 13:00 and 09:00 were statistically different from the minimum activity levels obtained at 21:00. Factor IX did not show a significant circadian variation.

Animals↗