Biomedical subjects

M Simard

Publications and source records attributed to M Simard.

At least 37 records · Page 2Linked to original sources

PubMed1999

Memory assessment in studies of cognition-enhancing drugs for Alzheimer's disease.

There is an increasing number of cognition-enhancing drugs for Alzheimer's Disease (AD) and, consequently, drug trials represent a growing field of interest in research. As memory dysfunction is generally the first and most severe cognitive impairment in AD, the choice of memory testing to be used in these studies is of great importance. It should reflect an understanding of memory systems being assessed with neuropsychological tests and the fact that some tests can be more appropriate than others to show benefit with certain classes of cognition-enhancing drugs. Severe deterioration of episodic and semantic memory occurs very early in the AD process while working memory shows a gradual deterioration over time. Some aspects of working and implicit memory can be spared in the mild to moderate stages of AD. Tests of working, episodic, semantic and implicit memory are used as outcomes in trials with acetylcholinesterase inhibitors, drugs with other neurotransmitter strategies, metabolic enhancers and drugs which may impact upon a variety of CNS processes. The clinical scales and observational measures are largely used in trials of cognition-enhancing drugs for AD (46.66% of all the studies reviewed). The Digit Span test, the Rey Auditory Verbal Learning Test, the Buschke Selective Reminding Test and the verbal fluency tasks are the most sensitive memory tests, whereas the most sensitive scales are the Sandoz Clinical Assessment-Geriatric, the Gottfried-Bräne-Steel scale and the Blessed Dementia Scale. Finally, we suggest that future investigations should use sensitive memory tests, together with behavioural and psychiatric scales, rather than general observational evaluations.

Alzheimer Disease↗

PubMed1999

Diagnosis of dementia and treatment of Alzheimer's disease. Pharmacologic management of disease progression and cognitive impairment.

OBJECTIVE: To highlight the importance of family physicians in the management of Alzheimer's disease (AD) and related dementias. To provide an update on the diagnostic workup of people with suspected dementia and on the pharmacologic management of cognitive impairment and disease progression in AD. QUALITY OF EVIDENCE: MEDLINE and Psychological Abstracts were searched using the terms "cognitive enhancers" or a specific drug name and "dementia (exp)." Evidence is generally limited but promising. Methodologic flaws in existing research likely to affect clinicians are briefly reviewed. MAIN MESSAGE: Increasing evidence suggests that early intervention can delay the progression of AD and improve the symptoms and function of those affected. Available treatments have modest but important effects on the outcome of patients with AD; some patients respond dramatically. Most currently available treatments are relatively safe in carefully selected cases. CONCLUSIONS: The diagnostic workup of most cases of dementia can at least be initiated in family physicians' offices. Beginning the workup is important because, for treating AD, the earlier you start, the better. Donepezil, vitamin E, and, in the near future, propentofylline are the main pharmacologic choices for improving cognition and slowing disease progression.

Aged↗

PubMed1999

Late-life depression as a possible predictor of dementia: cross-sectional and short-term follow-up results.

The authors explored cognitive functioning of a group of elderly subjects with depression. The group as a whole, and, in particular, the late-onset group (LOD), demonstrated cognitive impairment on the Mattis Dementia Rating Scale (MDRS). Subgroup differences were significant at P=0.004. This between-group difference was not seen when age and level of education were controlled. In the LOD group, 47.5% (vs. 31.5% of the early-onset group [P=0.025]), scored below the cutoff for dementia. Age-at-onset status in a logistic regression model predicted MDRS category, and treatment of the depression had little effect on cognition. Results support the hypothesis that late-life depression, particularly LOD, is associated with cognitive impairment that may represent early AD.

Age Factors↗

PubMed1999

The prediction and prevention of Alzheimer's disease--towards a research agenda.

This paper sets a research agenda for the prediction and prevention of future onset of Alzheimer's disease (AD). From a MEDLINE review of the literature, the authors found age to be a predictor of AD. The literature also indicates that memory and attentional impairments predict AD, although the relative risk is relatively low. Late-onset depression may also predict AD, but these data are limited by a lack of cohort studies. Studying cognitively impaired subjects with late-onset depression may identify a high-risk group, facilitating prevention trials. Characteristics of an "ideal" preventive agent are suggested. There is a biologic rationale, and preliminary evidence, that non-steroidal anti-inflammatory drugs (including ASA), estrogen and vitamin E may play a preventive role in AD. Other compounds (such as acetylcholinesterase inhibitors) are also promising, but costs, side effects, and lack of other health benefits may preclude their use in all but very high-risk groups.

Aged↗

PubMed1998

Kinetic study of host defense and inflammatory response to Aspergillus fumigatus in steroid-induced immunosuppressed mice.

The sequential pathogenesis of pulmonary aspergillosis was studied and the role of inflammatory cytokines in host response to Aspergillus fumigatus was characterized in immunocompetent and immunosuppressed mice. Two distinct phases were observed in immunocompetent mice: First, an intense clearance of A. fumigatus occurred, possibly through alveolar macrophages and recruited neutrophils (PMNL), accompanied by rapid release of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1beta, and second, cellular and fungal debris were cleaned by recruited monocytes, cytokine production rapidly decreased, and pneumonia self-healed. In contrast, cortisone-treated animals had, first, an altered clearance of conidia and delayed cytokine production and inflammatory cell recruitment; second, an invasive process in lungs, recruitment of PMNL, and release of IL-6 and IL-1beta; and third, widespread tissue necrosis, sustained release of IL-6 and IL-1beta, further increases in PMNL trafficking but no monocyte recruitment, respiratory failure, and 100% mortality within 5 days. These insights may be useful in the development of new treatment strategies for pulmonary aspergillosis.

Adrenal Cortex Hormones↗

PubMed1998

Reduction by cefodizime of the pulmonary inflammatory response induced by heat-killed Streptococcus pneumoniae in mice.

It has recently become apparent that overwhelming inflammatory reactions contribute to the high mortality rate associated with pneumococcal infection in immunocompetent hosts. Cefodizime (CEF) is an antibiotic that seems to be endowed with immunomodulating properties. To investigate the influence of CEF on the pulmonary inflammatory response induced by Streptococcus pneumoniae, we infected mice with repeated intranasal inoculations of 10(7) CFU of heat-killed fluorescein isothiocyanate-labeled bacteria, which are insensitive to the killing properties of the drug. CEF downregulated but did not abolish the strong polymorphonuclear leukocyte (PMN) recruitment induced by S. pneumoniae. PMN recruitment was not primarily mediated by leukotriene B4 in this model. The drug did not interfere with intrinsic mechanisms of phagocytosis by PMNs and alveolar macrophages. CEF totally abrogated the pneumococcus-induced tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) secretion in bronchoalveolar lavage fluid. The drug also prevented IL-6 release in lung homogenates and partly inhibited TNF-alpha, but it did not interfere with IL-1alpha secretion in the lungs of infected mice. The fractional and selective downregulation of inflammatory cells and cytokines by CEF suggests cell-specific and intracellular specific mechanisms of interaction of the drug. The immunomodulatory properties of CEF may help restrain excessive inflammatory reactions, thus contributing to the reported good clinical efficacy of the drug against lower respiratory tract infections.

Animals↗

PubMed1998

Immunomodulating effects of HMR 3004 on pulmonary inflammation caused by heat-killed Streptococcus pneumoniae in mice.

We investigated the influence of HMR 3004, a new ketolide antibiotic, on the pulmonary inflammation induced by heat-killed fluorescein isothiocyanate-labeled Streptococcus pneumoniae. HMR 3004 downregulated (P < 0.05) the pneumococcus-induced release of interleukin-6 (IL-6), IL-1beta, and nitric oxide in bronchoalveolar lavage fluid. The drug limited (P < 0.05) neutrophil recruitment to lung tissues and alveoli but did not interfere with phagocytosis. HMR 3004 totally abrogated lung edema. By reducing inflammation in addition to possessing antimicrobial properties, HMR 3004 may participate in improving the outcome of bacterial pneumonia.

Adjuvants, Immunologic↗

PubMed1998

Cytokine kinetics and other host factors in response to pneumococcal pulmonary infection in mice.

There is a need for more insight into the pathogenesis of Streptococcus pneumoniae pneumonia, as the fatality rate associated with this disease remains high despite appropriate antibiotherapy. The host response to pneumococci was investigated after intranasal inoculation of CD1 mice with 10(7) log-phase CFU of bacteria. We identified five major pathogenesis steps from initial infection to death. In step 1 (0 to 4 h), there was ineffective phagocytosis by alveolar macrophages, with concurrent release of tumor necrosis factor alpha (TNF), interleukin-6 (IL-6), and nitric oxide (NO) in bronchoalveolar lavage (BAL) fluid, TNF, IL-6, and interleukin-1 alpha (IL-1) in lung tissues, and IL-6 in serum, which were associated with tachypnea and hemoconcentration. In step 2 (4 to 24 h), bacterial growth in alveoli and polymorphonuclear cell recruitment from bloodstream to lung tissue (high myeloperoxidase levels) to alveoli were associated with high release of all three cytokines and leukotriene B4 (LTB4) in tissue and BAL fluid, as well as transient spillover of IL-1 in serum. In step 3 (24 to 48 h), despite downregulation of TNF and IL-1 in BAL fluid and lungs, there was appearance of injury to alveolar ultrastructure, edema to interstitium, and increase in lung weight as well as regeneration of type II pneumocytes and increased secretion of surfactant; bacteria progressed from alveoli to tissue to blood, and body weight loss occurred. In step 4 (48 to 72 h), strong monocyte recruitment from blood to alveoli was associated with high NO release in tissue and BAL fluid, but there was also noticeable lymphocyte recruitment and leukopenia; bacteremia was associated with TNF and IL-6 release in blood and thrombocytopenia. In step 5 (72 to 96 h), severe airspace disorganization, lipid peroxidation (high malondialdehyde release in BAL fluid), and diffuse tissue damage coincided with high NO levels; there was further increase in lung weight and bacterial growth, loss in body weight, and high mortality rate. Delineation of the sequential steps that contribute to the pathogenesis of pneumococcal pneumonia may generate markers of evolution of disease and lead to better targeted intervention.

Animals↗

PubMed1998

From a unidimensional to a bidimensional concept and measurement of workers' safety behavior.

OBJECTIVES: This study examines the concept and measurement of worker's safety behavior. It shows that the traditional concept of safety behavior centered on workers' carefulness or compliance with safety rules is limited and proposes that an additional dimension, namely, workers' safety initiatives, be taken into account. METHODS: Confirmatory factor analyses were carried out for a random sample of 828 workers drawn from 9 manufacturing facilities located in the province of Quebec (Canada). RESULTS: A 2-correlated congeneric factor model gave parameters in the expected direction, but the overall model was unable to reach a good fit. Separate construct analyses showed that compliance with safety rules is not a consistent dimension. The safety-initiatives dimension achieved a good fit with a high composite reliability (p=0.85). CONCLUSIONS: Workers' compliance with safety rules was not structured as a unitary dimension; therefore a selective process of safety-rules compliance by workers is suggested. Each category of safety rules should be considered as 1 single dimension and measured by several specific indicators. Indicators for safety initiatives provide high reliability, and, since this dimension is an important predictor of effectiveness in accident prevention, the items tested provide a better measurement than those previously published.

Accidents, Occupational↗

PubMed1997

Differential distributions in tissues and efficacies of aztreonam and ceftazidime and in vivo bacterial morphological changes following treatment.

The differential tissue distributions of aztreonam and ceftazidime within fibrin clots infected with Pseudomonas aeruginosa, Enterobacter cloacae, and Serratia marcescens, their efficacies, and the in vivo bacterial morphological changes induced by these drugs were evaluated. Rabbits were given intravenously a single dose of 100 mg of either agents/kg of body weight. In the cores of the clots, the peak levels of both drugs were much lower than those observed in the peripheries and in serum. Aztreonam's half-lives within the peripheries and in the cores of the fibrin clots were up to six times higher than observed in serum, while ceftazidime's half-lives in clots were twice that observed in serum. This resulted in a much greater penetration ratio for aztreonam than for ceftazidime. Both drugs controlled the growth of P. aeruginosa in vivo, but E. cloacae and S. marcescens responded better to ceftazidime. Morphological changes were more abundant in the peripheries than in the cores of the clots. In the control group, P. aeruginosa's morphology in the cores was different than that in the peripheries of the clots. Against P. aeruginosa, aztreonam did induce morphological changes in the cores while ceftazidime did not. Electron microscopic studies revealed that morphological changes associated with aztreonam seemed different than those of ceftazidime. Along with elongation of bacteria, more bow tie and herniated bacteria were observed with aztreonam. Though both agents selectively affect PBP 3, as manifested by elongated bacteria, they induce in the peripheries of the clots thickening, breaks, and detachment in bacterial cell walls, alterations which are generally associated with antibiotics affecting PBP 1a and 1b.

Animals↗

PubMed1997

[No relationship between tacrine cytotoxicity and its metabolisation by cytochrome P4501A2].

It has been suggested that tacrine (THA) induced hepatotoxicity was related to its metabolic pathway involving cytochrome P4501A2 (CYP1A2). Using a model of genetically modified cells we have demonstrated that THA induced a marked decrease in cell viability and a strong inhibition of RNA and protein synthesis. However, these cytotoxic effects did not differ in parental Chinese hamster V79 cells and variant cells expressing human or rat CYP1A2 as well in human HepG2 and Chang Liver cells despite their notable metabolism ability to metabolize THA to hydroxylated metabolites. These results strongly suggest that THA-induced cytotoxicity is not mediated by CYP1A2 indicating that THA could be toxic by direct inhibition at the ribosomial level.

Analysis of Variance↗

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

Ontogeny of growth hormone receptors in human tissues: an immunohistochemical study.

Both experimental and clinical studies suggest that human GH (hGH) may have a functional role during early stages in human development. To determine when receptors for hGH appear in specific target cells, we carried out an immunohistochemical analysis of six tissues obtained from 20 fetuses (8.5-20 weeks fetal age [FA]), two term infants, one 11-yr-old male, and one 43-yr-old male. Liver parenchymal and bile duct cells showed specific staining from the earliest FA examined (8.5 weeks); in fetal liver, the intensity of the immunoreaction was greatest in hepatocytes surrounding the central veins and portal triads, whereas the numerous hematopoietic cells exhibited little to no immunostaining. Kidney tissues also showed positive localization at 8.5-9 weeks FA. By 13 weeks, epithelial cells of most tubules were immunoreactive, with medullary tubules showing stronger staining than those in the cortex, whereas visceral epithelial cells of glomeruli were weakly positive; metanephrogenic blastemal cells were negative. A similar immunostaining pattern was observed in midgestation and postnatal kidneys, except that glomerular staining was lost by 19 weeks FA. Fetal zone cells of fetal adrenals showed weak immunostaining beginning at 13-14 weeks; glomerulosa cells stained intensely in the postnatal adrenal. Epithelial crypt cells in both small and large intestine immunostained beginning at 19-20 weeks; a similar pattern was observed in postnatal sections. Dermal fibroblasts and skeletal muscle of abdominal skin were positive from 8.5 weeks. Epidermal cells first showed immunostaining at 13-14 weeks; germinal layer cells showed the most intense reaction until 19-20 weeks, when the staining pattern became uneven throughout the epidermal layers. Epithelial cells in hair follicles and sebaceous glands were positive from 13-14 weeks; by 19-20 weeks, these cells were the most intensely immunostained in skin sections. Lung tissue was negative from 8.5-20 weeks, as well as postnatally. Vascular endothelial and smooth muscle cells routinely stained from 8.5 weeks FA in all tissues examined. We conclude that immunoreactive hGH receptors can be identified in early fetal, as well as postnatal, tissues and that the pattern of cellular immunostaining develops gradually throughout gestation in a very tissue-specific manner.

Adult↗

PubMed1996

Ribavirin potentiates the efficacy and toxicity of 2',3'- dideoxyinosine in the murine acquired immunodeficiency syndrome model.

The efficacy and toxicity of ribavirin (25 or 125 mg/kg/day), 2',3'-dideoxyinosine (ddI) (200 mg/kg/day) and a combination of both drugs at these doses given for 6 weeks were investigated in the murine acquired immunodeficiency syndrome model. Our results showed a significant protection against splenomegaly, lymphadenopathy and hypergammaglobulinemia in mice treated with ribavirin at 25 mg/kg/day alone or in combination with ddI at 200 mg/kg/day. A good synergistic effect was observed with the drug combination, whereas ddI alone (200 mg/kg/day) did not give any protection. Ribavirin/ddI combination protected against the loss of CD8 T cells in spleen and restored the capacity of splenocytes to proliferate after activation with a mitogenic agent. Moreover, the drug combination resulted in a protection of the spleen and cervical lymph node architectures and a regression of germinal centers. Hematotoxicity appeared at a dose of 125 mg/kg of ribavirin alone and increased when used concomitantly with ddI. In conclusion, ribavirin and ddI at low doses are synergistic and effective in the murine acquired immunodeficiency disease model, but at high doses they are toxic.

Animals↗

PubMed1995

Protection against gentamicin nephrotoxicity by daptomycin in nephrectomized rats.

Daptomycin was previously shown to reduce gentamicin renal toxicity and this toxicity was not delayed by the concomitant injection of daptomycin (Thibault N., L. Grenier, M. Simard, M. G. Bergeron, and D. Beauchamp, Antimicrob. Agents Chemother., 38 1027-1035 (1994)). The protective effect of daptomycin against gentamicin toxicity was evaluated in 96 female Sprague-Dawley rats. Normal and nephrectomized rats were treated with saline (NaCl, 0.9%), gentamicin (30 mg/kg/12 hrs, i.p.), daptomycin (10 mg/kg/12 hrs, s.c.) or with a combination of daptomycin plus gentamicin during 4 and 10 days. On day 4, gentamicin and daptomycin cortical levels were higher in nephrectomized gentamicin-daptomycin-treated rats (p < 0.05) as compared to all other groups. The accumulation of gentamicin or daptomycin in nephrectomized gentamicin-daptomycin-treated or gentamicin-saline-treated rats was higher on day 4 (p < 0.01) than on day 10. Other parameters such as the sphingomyelinase activity in the renal cortex, the serum creatinine, and the histopathology showed significantly fewer changes in daptomycin-gentamicin-treated rats as compared to animals given gentamicin alone. On the other hand, the protection of daptomycin was less extensive in nephrectomized rats as compared to normal rats. Daptomycin and gentamicin were localized in the lysosomes of proximal tubular cells of animals treated with daptomycin and gentamicin given alone or in combination. These results suggest that daptomycin protects against gentamicin toxicity in nephrectomized rats but to a lesser extent than in normal rats.

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↗

PubMed1994

Subcellular distribution of daptomycin given alone or with tobramycin in renal proximal tubular cells.

Previous studies in experimental animals showed that daptomycin, a lipopeptide antibiotic, protects against aminoglycoside nephrotoxicity (C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. N. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989; D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew, and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990). In order to better understand the mechanism involved in this protective effect, the subcellular distribution of daptomycin was investigated in the proximal tubular cells of animals treated with daptomycin alone or in combination with tobramycin. A first group of female Sprague-Dawley rats received a single intravenous injection of daptomycin at a dose of 100 mg/kg of body weight and were killed at 10 min, 1 h, or 24 h after the injection. Other groups of rats were treated during 10 days with saline (NaCl, 0.9%), tobramycin at dosages of 20 mg/kg/12 h, daptomycin at dosages of 10 mg/kg/12 h, or the combination tobramycin-daptomycin at the same dosages. At the time of sacrifice, the renal cortex of the right kidney of each animal was dissected, and small blocks of tissue were fixed, dehydrated, and embedded in Araldite 502 epoxy resin. The subcellular distribution of daptomycin and tobramycin was determined on ultrathin sections by immunogold labeling. Ten minutes after the injection of daptomycin alone, gold particles were seen over the brush border membrane and on the membranes of the endocytic vacuoles of proximal tubular cells. One hour after the injection, a similar distribution was seen and numerous gold particles were found over the lysosomes of proximal tubular cells. The results suggest that daptomycin might protect against aminoglycoside nephrotoxicity by interfering with the interaction between the aminoglycoside and phospholipids inside the lysosomes of proximal tubular cells.

Animals↗

PubMed1994

Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin.

The lipopeptidic antibiotic daptomycin is reported to reduce experimental tobramycin nephrotoxicity (D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. C. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989). In an attempt to explain these results, the in vivo and in vitro interactions between daptomycin and tobramycin were studied. Tobramycin alone and preincubated with negatively charged phospholipid bilayers (liposomes) was dialyzed against increasing concentrations of daptomycin in buffer at pH 5.4. A significant drop in the concentration of tobramycin was observed when daptomycin was added to the opposite half cells. Furthermore, daptomycin induced a concentration-dependent release of lipid-bound tobramycin. Gold labeling experiments showed that daptomycin could be incorporated into phospholipid layers. Female Sprague-Dawley rats were treated with daptomycin alone, with tobramycin alone, or with the combination over 2 to 10 days. Levels of daptomycin and tobramycin in serum were similar in all groups. The levels of tobramycin in the renal cortex increased significantly with time and, on day 10, reached values of 654 +/- 122 and 844 +/- 298 micrograms/g of tissue (mean +/- standard deviation; not significant) in animals treated with tobramycin and the combination of daptomycin-tobramycin, respectively. No significant difference was observed in the levels of tobramycin in the kidneys between animals treated with tobramycin or the daptomycin-tobramycin combination at any time. By contrast, daptomycin levels were significantly higher in the renal cortexes of animals treated with daptomycin-tobramycin in comparison with those in the renal cortexes of animals treated with daptomycin alone on days 6,8, and 10 (P < 0.01). For immunogold labeling studies, animals were killed 4 h after a single injection of daptomycin alone or daptomycin in combination with tobramycin. Daptomycin was found throughout the matrixes of the lysosomes of proximal tubular cells of animals treated with daptomycin alone. In animals treated with the combination of daptomycin and tobramycin, daptomycin was associated with intralysosomal myeloid bodies. Our results suggest that daptomycin might attenuate experimental aminoglycoside nephrotoxicity by interacting with the aminoglycoside, perhaps electrostatically, and thereby protecting intracellular targets of toxicity.

Animals↗