Gentamicin disposition kinetics in humans with spinal cord injury

Segal, Jack L.; Gray, David; Gordon, S; Eltorai, Ibrahim M.; Khonsari, Feraidoun; Patel, Jamie

doi:10.1038/sc.1985.8

Cited by 22 publications

(35 citation statements)

References 11 publications

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“…The present results, as well as those reported elsewhere by our group 4,[12][13][14][15] and other researchers, [5][6][7][8][9][10] clearly indicate that pharmacokinetics of a given drug can exhibit important differences in patients with SCI compared with able-bodied individuals. An adequate understanding of these phenomena is warranted, and therefore further research is still required.…”

Section: Discussionsupporting

confidence: 79%

“…Significant changes in volume of distribution and clearance have been reported in patients after cord lesion for various drugs, including aminoglycosides 5 and methylprednisolone. 6 Likewise, SCI-induced changes in oral drug absorption have been reported for paracetamol, 4,7 dantrolene 8 and theophylline, 9 and it has been suggested that these changes could have an impact on the efficacy and safety of a variety of drugs in this population. 10 Characterization of the pathophysiological alterations underlying pharmacokinetic changes that occur in patients with SCI has been complicated because of the important variability induced by differences in injury characteristics, as well as in the individual conditions of each patient.…”

Section: Introductionmentioning

confidence: 99%

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Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction

et al. 2012

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Study design: Laboratory investigation in rats submitted to experimental spinal cord injury (SCI). Objective: To determine the effect of acute SCI on the pharmacokinetics of diclofenac, a marker drug of intermediate hepatic extraction, administered by the intravenous and the oral routes. Methods: Female Wistar rats were submitted to complete section of the spinal cord at the T8 level. SCI and sham-injured rats received 3.2 mg kg À1 of diclofenac sodium either intravenously or orally, diclofenac concentration was measured in whole blood samples and pharmacokinetic parameters were estimated. Diclofenac was not selected as test drug because of its therapeutic properties, but because to its biopharmaceutical properties, that is, intermediate hepatic extraction. Results: Diclofenac bioavailability after intravenous administration was increased in injured rats compared with controls due to a reduced clearance. In contrast, oral diclofenac bioavailability was diminished in SCI animals due to a reduction in drug absorption, which overrides the effect on clearance. Conclusion: Acute SCI induces significant pharmacokinetic changes for diclofenac, a marker drug with intermediate hepatic extraction. SCI-induced pharmacokinetic changes are not only determined by injury characteristics, but also by the route of administration and the biopharmaceutical properties of the studied drug.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction

et al. 2012

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“…These drugs present an increased bioavailability due to impaired hepatic metabolic clearance. 30,43,49 Experimental studies have shown that increasing hepatic microvascular blood flow through nitric oxide-mediated vasodilation using L-arginine, a nitric oxide precursor, could ameliorate PK alterations at this level. 50 …”

Section: Altered Pkmentioning

confidence: 99%

Spinal cord injury sequelae alter drug pharmacokinetics: an overview

et al. 2011

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Study design: Literature review. Objectives: Critical review of the literature published on the physiological alterations caused by spinal cord injury (SCI) and their effect on the pharmacokinetic parameters of commonly employed drugs. The review introduces the most recent treatment protocols of a variety of drugs, enabling the modern clinician to apply efficacious and cost-effective solutions to the pharmacological treatment of SCI patients. Methods: Studies published in international indexed journals up to January 2011 were selected from the PubMed database. Results: The review evaluated the sequelae of SCI and their effect on pharmacological processes. The results demonstrated that these alterations affected the pharmacokinetics of drugs commonly administered to SCI patients, such as antibiotics, muscle relaxants, immunosuppressants and analgesics. Conclusion: There are multiple etiologies to SCI and patients present with varying degrees of impairment. Factors such as level of injury and completeness of the injury create a very heterogeneous population within the SCI community. The heterogeneity of this population creates a problem when trying to standardize pharmacokinetic (PK) parameters. It is because of this that specific physiological alterations must be linked to changes in PK and be identified within the clinical setting. This relationship between physiology and PK enables the clinician to be alert for possible pharmacological complications in individual patients based on their clinical manifestations. Future research should aim to develop rigorous therapeutic guidelines tailored to the diverse manifestations of SCI so as to provide effective, affordable and safe pharmacotherapy.Spinal Cord (2011) 49, 955-960;

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“…A reduced delivery of antibiotics into paralyzed areas could contribute as well because of changes that can be detected within 1 week of spinal cord injury, including the following: (i) elevation of interstitial tissue pressure and decreased blood flow (16); (ii) increase in extracellular volume of distribution caused by erosion of muscle mass and decreased venomotor tone (15); (iii) protein catabolism in peripheral tissues (4,7,12).…”

Section: Discussionmentioning

confidence: 99%

Cephalosporin penetration into soft tissue of paralyzed limbs

Darouiche

Musher

Hamill

et al. 1989

Antimicrob Agents Chemother

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Poor penetration of antibiotics into paralyzed tissue may contribute to the difficulty of curing soft tissue infections in paralyzed limbs. A novel model of spinal cord hemisection was used to induce paralysis of one hind leg in mice. Five, 10, or 20 days after induction of paralysis, six groups of 10 mice were injected intravenously with a single dose or with four sequential doses of cefepime, a new broad-spectrum cephalosporin, and then sacrificed. High-performance liquid chromatography was used to compare cefepime levels in soft tissue homogenates of paralyzed and normal hind legs; no significant differences were found in any group. Factors other than antibiotic delivery may be responsible for difficulty in curing infections in paralyzed soft tissue.Soft tissue infections frequently occur in patients with spinal cord injury and are difficult to treat (5,17,18). Reduced delivery of antibiotics to paralyzed tissue could be responsible, although local factors may also play a role (11). We elected to investigate the effect of paralysis on antibiotic distribution by developing a hitherto undescribed mouse model that caused unilateral paralysis of one hind leg. By using high-performance liquid chromatography, we measured the concentration of cefepime, a new broad-spectrum cephalosporin, in soft tissue homogenates, comparing in each mouse the paralyzed limb with the normal limb. MATERIALS AND METHODSAnimals. Swiss albino Sprague-Dawley mice (approximate weight, 30 g) were used. Mice were anesthetized with methoxyflurane (Pitman-Moore Inc., Washington Crossing, N.J.), and a 0.5-cm incision was made over the midthoracic spine of each mouse. A #15 scalpel blade was gently introduced posterolaterally through soft tissue into the vertebral column. The scalpel was aimed medially to achieve hemisection of the spinal cord. Unilateral paralysis of one hind leg occurred in nearly one-half of the mice; approximately one-third of these animals regained function in the paralyzed leg within a few days, and these were excluded from the study. Cages were modified to provide easy access to food and water.Experimental design. Five, 10, or 20 days after induction of paralysis, groups of 10 mice each were injected intravenously with a single dose, or with four doses at 1-h intervals, of 200 mg of cefepime (Bristol-Myers Company, Wallingford, Conn.) per kg. A pilot study had shown that the serum half-life of cefepime in mice was about 17 min. At 1 h after the last cefepime dose, mice were anesthetized and sacrificed by aspirating as much blood as possible via a cardiac puncture. The heart and great vessels were then severed in order to minimize blood in the peripheral tissue. After removing overlying skin and subcutaneous tissues, both hind legs were resected, rinsed to remove adhering blood, and blotted dry. The soft tissue, which consisted largely of muscle, was dissected from bone, minced, weighed, and placed in polypropylene tubes (17 by 100 mm). Phosphatebuffered saline was added in a volume:weight ratio of 3:1. * Corresponding aut...

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Gentamicin disposition kinetics in humans with spinal cord injury

Cited by 22 publications

References 11 publications

Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction

Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction

Spinal cord injury sequelae alter drug pharmacokinetics: an overview

Cephalosporin penetration into soft tissue of paralyzed limbs

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