Microcirculation and blood volume in rats before and after spinal cord injury

Seifert, J.; Lob, G.; Probst, J.; Brendel, W.

doi:10.1038/sc.1979.85

Cited by 9 publications

(5 citation statements)

References 5 publications

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“…[17][18][19] During spinal shock, there is low circulation volume and low cardiac output, which importantly contribute to decrease blood flow to non-vital organs, including liver. 15,[20][21][22] This could lead to significant changes in drug distribution and elimination, particularly for highextraction drugs.…”

Section: Discussionmentioning

confidence: 99%

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Acute spinal cord injury changes the disposition of some, but not all drugs given intravenously

Garcı́a-López

Martínez-Cruz²,

Guı́zar-Sahagún

et al. 2006

Spinal Cord

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Study design: Experimental laboratory investigations in paraplegic rats. Objective: In order to understand why acute spinal cord injury (SCI) changes the disposition of some, but not all drugs given intravenously (i.v.), pharmacokinetic parameters of drugs with different pharmacological properties were evaluated to determine the influence of SCI on physiological processes such as distribution, metabolism and excretion. Setting: Mexico City, Mexico. Methods: Rats were subjected to severe SCI (contusion) at T-9 level; pharmacokinetic studies of phenacetin, naproxen or gentamicin were performed 24 h after. These drugs were not chosen as markers because of their therapeutic properties, but because of their pharmacokinetic characteristics. Additional studies including plasma proteins, liver and renal function tests, and micro-vascular hepatic blood flow, were also performed at the same time after injury. Results: Acute SCI significantly reduced distribution of drugs with intermediate and low binding to plasma proteins (phenacetin 30% and gentamicin 10%, respectively), but distribution did not change when naproxen -a drug highly bound to plasma proteins (99%) -was used, in absence of changes in plasma proteins. Metabolism was significantly altered only for a drug with liver blood flow -limited clearance (phenacetin) and not for a drug with liver capacity-limited clearance (naproxen). The liver function test did not change, whereas the hepatic micro-vascular blood flow significantly decreased after SCI. Renal excretion, evaluated by gentamicin clearance, was significantly reduced as a consequence of SCI, without significant changes in serum creatinine. Conclusions: Changes in drug disposition associated to acute SCI are complex and generalization is not possible. They are highly dependent on each drug properties as well as on the altered physiological processes. Results motivate the quest for strategies to improve disposition of selective i.v. drugs during spinal shock, in an effort to avoid therapeutic failure.

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Section: Discussionmentioning

confidence: 99%

“…These changes could be explained by alteration in renal blood-flow during spinal shock 15,20 and consequently the alteration in glomerular filtration. 24,25 Results on serum creatinine of this study suggest that a global renal failure is not involved.…”

Section: Disposition Of Unchanged Drugs Which Elimination Depends On mentioning

confidence: 99%

Acute spinal cord injury changes the disposition of some, but not all drugs given intravenously

Garcı́a-López

Martínez-Cruz²,

Guı́zar-Sahagún

et al. 2006

Spinal Cord

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“…The lower clearance of riluzole at the start of treatment compared with day 14 can be attributed to the decreased hepatic microvascular blood flow and hepatocyte gene expression immediately following the injury. Immediately following neurogenic shock, there is low circulation volume and low cardiac output, which contribute to the decreased microvascular blood flow in the liver, spleen, and skeletal muscle 19,22 . The reduction is likely from redirection of blood flow to maintain an adequate perfusion of the brain and heart 23 .…”

Section: Discussionmentioning

confidence: 99%

“…Immediately following neurogenic shock, there is low circulation volume and low cardiac output, which contribute to the decreased microvascular blood flow in the liver, spleen, and skeletal muscle. 19 , 22 The reduction is likely from redirection of blood flow to maintain an adequate perfusion of the brain and heart. 23 Biotransformation of drugs depends on the amount of drug arriving in the liver and the expression of cytochrome P450, both of which require adequate hepatic blood flow.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent

Nguyen

Chow

et al. 2021

The Journal of Clinical Pharma

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Riluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A 1-compartment with first-order elimination population pharmacokinetic model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the phase 1 and the ongoing phase 2/3 trials. This change in therapeutic exposure may lead to a biased estimate of the exposure-response relationship when evaluating therapeutic effects. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification that preserves the required therapeutic exposure of riluzole.

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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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Microcirculation and blood volume in rats before and after spinal cord injury

Cited by 9 publications

References 5 publications

Acute spinal cord injury changes the disposition of some, but not all drugs given intravenously

Acute spinal cord injury changes the disposition of some, but not all drugs given intravenously

Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent

Cephalosporin penetration into soft tissue of paralyzed limbs

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