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Fampridine SR (4-aminopyridine) is a potassium channel-blocking drug currently being investigated for its therapeutic efficacy in ameliorating central conduction deficits due to demyelination in patients with spinal cord injury (SCI). The present open-label pharmacokinetic trial examined the absorption characteristics of a sustained-release form of the drug in 25 SCI subjects with chronic incomplete injuries. The overall group mean Cmax of 27.7 +/- 6.2 ng/mL occurred at a tmax of 3.4 +/- 1.4 hours. AUC0-12 was 210.5 +/- 49.5 ng/mL.h. For paraplegics, AUCtmax was 76.02 +/- 33.28 and for tetraplegics was significantly less at 51.25 +/- 20.36 (p = 0.037). A statistically significant difference in the initial rate and extent of absorption, but not in total 4-AP bioavailability over the 12-hour study period, was evident between tetraplegic patients, 0.60 +/- 0.23, and paraplegic patients, 0.39 +/- 0.14 (p = 0.02). There was a linear correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax. These results confirm and extend previous observations of different rates of drug absorption among SCI patients with lesions above and below the sympathetic outflow (T6) and provide evidence of the absorption characteristics of this sustained-release form of 4-aminopyridine, which is helpful for optimal dosing.

Study Objective: To determine the effects of the long-term administration of 4-aminopyridine (4-AP) on sensorimotor function in humans with long-standing spinal cord injury (SCI)., Design: Randomized, open-label, active-treatment control, dosage-blinded study., Setting: University-affiliated, tertiary-level care, Department of Veterans Affairs Medical Center., Patients: Twenty-one healthy men and women outpatients suffering from traumatic SCI (14 tetraplegic, 7 paraplegic) for 2 years or more., Interventions: Dosages of an immediate-release formulation of 4-AP were titrated. At 3 months, 16 subjects were receiving 4-AP 30 mg/day (high dose); 5 subjects were receiving 4-AP 6 mg/day (low dose) and served as an active-treatment control group., Measurements and Main Results: Composite motor and sensory scores had statistically significant increases at 3 months. Maximal expiratory pressure, maximal inspiratory pressure, forced vital capacity, and forced expiratory volume in 1 second showed clinically meaningful and/or statistically significant increases among patients receiving 4-AP 30 mg/day. These subjects also had significant decreases in spasticity (modified Ashworth Scale). Serial biochemical profiles and electroencephalographs were unchanged from baseline, and no clinically significant drug toxicity was encountered., Conclusions: Long-term oral administration of immediate-release 4-AP was associated with improvement in and recovery of sensory and motor function, enhanced pulmonary function, and diminished spasticity in patients with long-standing SCI. 4-Aminopyridine appears to be safe and relatively free from toxicity when administered orally over 3 months. Each patient who received immediate-release 4-AP 30 mg/day showed a response in one or more of the outcome measures.

Spinal cord injury (SCI) patients are known to suffer from autonomic failure as a result of their injury. The magnitude of the dysautonomia resulting from such an injury is difficult to predict or characterize and, in varying degree, it impedes the recovery of physiological homeostasis. This study is intended to investigate the effectiveness of heart rate variability (HRV) analysis as a method of quantifying and characterizing autonomic function in patients with traumatic spinal myelopathy. HRV analysis was carried out in 13 male SCI patients (six tetraplegic, seven paraplegic) and 13 age-matched, able-bodied controls. Twenty-four hour ambulatory and sleep ECG tracings were obtained. Time domain, amplitude, and power spectral analyses were used to study HRV and autonomic function. Both tetraplegic (20+/-12 ms, mean+/-SD) and paraplegic (22+/-8 ms) subjects demonstrated significant loss of low frequency 24-hour HRV compared to able-bodied controls (36+/-14 ms, p < 0.05) and during sleep. This was interpreted as being consistent with predominantly sympathetic denervation uninfluenced by degree of physical activity. There were no significant differences between groups in parasympathetically mediated high frequency HRV. We conclude that HRV analysis is capable of distinguishing between SCI or able-bodied humans and among tetraplegic and paraplegic patients. Patterns of altered HRV may be useful in more completely characterizing or stratifying changes in physiology associated with injury level and may have diagnostic, prognostic, or therapeutic significance.

Recovery of useful motor function in humans with spinal cord injury (SCI) is a primary and elusive goal. In this preliminary study, we describe efforts to delineate the pharmacological effects of 4-aminopyridine (4-AP) on gait parameters in spinal cord injured humans who have retained some capacity to ambulate bipedally. A sequential entry, open label study was made of the effects of a single oral administration of an immediate-release formulation of 4-AP on the time-course profile of changes in component parameters of bipedal gait in ambulatory volunteers with chronic SCI. Nine healthy, rehabilitated, community-adapted male volunteers (six tetraparetic, three paraparetic), who sustained their injuries more than one year prior to entry into the study, ingested a single 10-mg dose of 4-aminopyridine after an overnight fast. Gait analysis parameters included velocity (meters/min), cadence (steps/min), stride length (meters), gait cycle (seconds), and double limb support (percent of gait cycle). They were measured for 24 hours using a sampling-rich strategy (nine duplicate measurements over 24 hrs). Repeated measures (randomized block) analysis of variance (ANOVA) and paired t-tests were used to test for the significance of differences between means and variances. The apparent pharmacological effect of 4-AP is associated with statistically significant changes in one or more of the component elements used to assess the characteristics and efficiency of bipedal gait. These changes in gait analysis parameters correspond temporally with the improvements in pulmonary function and heart rate variability previously described by us. 4-AP appears to enhance gait in a subset of humans with SCI. In this preliminary study we report, for the first time, an apparent effect of 4-AP on gait in spinal cord injured humans and suggest that the pharmacological effects of 4-AP may have clinically significant application in the restoration of useful motor function.

Study Objective: To evaluate the pharmacokinetics of high-dose methylprednisolone in patients with acute spinal cord injury (ASCI)., Design: Open-label study of consecutive patients with ASCI, and retrospective review of able-bodied controls., Setting: Emergency Medicine Department of a large, urban, university-affiliated, tertiary care trauma center., Patients: Eleven men with ASCI., Interventions: Methylprednisolone sodium succinate 30 mg/kg intravenous bolus, followed by 5.4 mg/kg/hour for 23 hours, administered according to the second National Acute Spinal Cord Injury Study (NASCIS 2) protocol., Measurements and Main Results: The total systemic clearance of methylprednisolone was significantly less in acutely injured patients (mean +/- SD 30.04 +/- 12.03 L/hr) than in historically reported able-bodied controls (44.70 +/- 4.90 L/hr). An inverse correlation between the neurologic level of injury and systemic clearance was seen. No differences in volume of distribution were discernible between patients (126.90 L) and controls (135.45 L)., Conclusion: Patients with acute spinal cord injury administered methylprednisolone according to the NASCIS 2 protocol had an apparent decrease in total systemic clearance of the drug without a commensurate change in volume of distribution. Additional studies are warranted to confirm these findings and assess the potential impact of diminished clearance on the efficacy of the agent in ASCI.

Study Objective: To test the hypothesis that 4-aminopyridine (4-AP) might cause clinically evident improvement in pulmonary function in humans with chronic spinal cord injury (chronic SCI)., Design: Balanced, open-label study with subjects consecutively enrolled., Setting: Spinal Cord Injury Service, university-affiliated tertiary level care Department of Veterans Affairs Medical Center., Patients: Seventeen healthy men and women suffering from traumatic SCI (11 quadriplegic, 6 paraplegic patients) for more than 1 year., Interventions: Each subject was given a single dose of 4-AP 10 mg orally in an immediate-release formulation., Measurements and Main Results: Significant increases in mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) that persisted for at least 12 hours were demonstrated in quadriplegic patients beginning 6 hours after 4-AP administration. Tests of pulmonary function that demonstrated statistically significant increases at any time were also numerically, if not statistically, increased at 24 hours compared with pretreatment values obtained in 4-AP-naive subjects., Conclusions: The administration of a single dose of an immediate-release formulation of 4-AP to humans with longstanding, traumatic quadriplegia is associated with sustained, clinically meaningful, and statistically significant improvements in pulmonary function. We suggest that the administration of 4-AP may have a salutary effect in patients suffering from SCI and appears to be associated with potentially clinically significant reductions in the pathophysiologic pulmonary sequelae of SCI.

Objective: To measure circulating levels of well-studied, easily quantifiable surrogate markers or mediators of inflammation and tissue remodeling in patients with spinal cord injury (SCI) suffering from pressure ulcers. Cytokines or their receptors, eg, interleukins IL-6 and IL-2, IL-2R (the soluble interleukin-2 receptor), and the intercellular adhesion molecule ICAM-1, are mediators of immune response, inflammatory processes, and tissue remodeling involving the skin and other organs. Activation of these immune effectors and their accumulation in tissue can be associated with pathological changes or healing, and elevated plasma concentrations can indirectly reflect the magnitude of immune activation., Design: Participants were consecutively enrolled in a controlled, gender-specific study of the relationship between circulating IL-1 beta, IL-2, IL-2R, and ICAM-1 and pressure ulcers in patients with chronic SCI., Setting: The department of medicine of a university-affiliated medical center and the spinal cord injury service at a Department of Veterans Affairs medical center., Patients or Other Participants: Seventy men with longstanding SCI (19 with pressure ulcers). The mean age was 49 +/- 14 (range 25 to 74 years). Duration of SCI ranged between 1 and 46 years, and the level of injury varied from C2 to L5. The control group consisted of 20 healthy, able-bodied volunteers (10 men and 10 women aged 25 to 50 years)., Main Outcome Measures: Circulating plasma levels of IL-6, IL-2, IL-2R, and ICAM-1 and their relation to the rate of wound healing in subjects with SCI., Results: Plasma concentrations of bioactive molecules IL-6, IL-2R, and ICAM-1 were numerically or significantly elevated in all patients with SCI as compared to able-bodied individuals. The greatest increase in concentration was seen in those patients with pressure ulcers who demonstrated slow healing of their wounds., Conclusions: SCI and trauma to insensitive tissue result in immunoactivation. In patients with SCI and pressure ulcers, elevated levels of circulating ICAM-1 and IL-2R may have diagnostic, prognostic, and therapeutic value in predicting or differentiating subgroups of patients who will vary in the severity or the rate of healing of their wounds.

A study was conducted to determine the effect of metoclopramide on the disposition of dantrolene in patients with spinal cord injury (SCI) and in neurologically intact, able-bodied volunteers. Fifteen serum samples each were collected from 6 able-bodied volunteers and 13 patients with SCI (7 paraplegics, 6 quadriplegics) in a prospective, open-label, pharmacokinetic study of a single 100-mg oral dose of dantrolene. After a washout period, a single 10-mg intravenous dose of metoclopramide was given along with dantrolene to the patients with SCI only, and the study was repeated in sequential, crossover fashion. Concentrations of dantrolene were measured by a high-performance liquid chromatography (HPLC) assay. Numerical integration was used to calculate area under the curve (AUC) and mean residence time (MRT). Differences were studied using paired and two-sample, nonparametric tests, with 0.05 as the significance level. Without metoclopramide, the AUC of dantrolene was larger in able-bodied volunteers than in patients with SCI, and the MRT of dantrolene was similar both groups. When patients with SCI received metoclopramide before treatment with dantrolene, the median increase in the AUC for dantrolene was 57%, with no change in MRT. This pharmacokinetic interaction is probably attributable to augmented absorption and could alter the pharmacologic action of dantrolene. Concurrent treatment of patients with SCI with metoclopramide and dantrolene should be accompanied by careful surveillance to avoid toxicity and preserve efficacy.

Objectives: The rate and completeness of gastric emptying (GE) are major determinants of the bioavailability of oral medication, and the efficiency of gastric emptying is highly dependent on an intact central nervous system. Hence, in spinal cord injury (SCI), an impairment in gastric emptying could significantly diminish drug efficacy., Methods: We evaluated posture-dependent (seated and supine) gastric emptying of an isotopically-labeled liquid meal in six quadriplegic subjects. The time-course profile of the gastric elimination of a radionuclide was followed for up to 120 min using serial anterior scintigraphy, and the disappearance of radioactivity from the stomach was described by both a mono- and biexponential fit of raw data. A half-time of gastric emptying (GEt1/2) was estimated from each curve and compared to GEt1/2 derived from able-bodied (intact neuraxis) experimental and historic control populations., Results: The mean GEt1/2 in quadriplegic subjects (monoexponential curve fit) was significantly increased to 43.4 +/- 26.0 min in seated SCI subjects (95% CI 13.5-73.2, p < 0.05) and to 50.5 +/- 48.0 min in supine SCI subjects compared to supine experimental and historic control values of 10.1 +/- 8.8 min (95% CI 2.3-18.0, p < 0.05) or 12.0 +/- 3.0 min (95% CI 9.4-14.8, p < 0.05), respectively. A small, non-significant trend towards an increased rate of GE (decreased GEt1/2) was observed in seated SCI subjects., Conclusions: We conclude that gastric emptying is impaired in subjects with cervical SCI. Comparative studies of gastric emptying in subjects with SCI should incorporate concurrently studied, control subjects and employ experimental methods that are not constrained by truncated data collection periods. The convention of forcing GE data to conform to a monoexponential pattern of evacuation ignores time-dependent multiphasic patterns of GE and does not support serendipity.

The authors report the data obtained from their experience in acetabular reimplantation using an Eichler ring and cemented cup. The ring that may also be applied indifferently by the prosthetic stem component, allows complete reconstruction of the anatomical border of the acetabulum even when there has been a considerable loss of substance. Long-term follow-ups have shown that by using Eichler rings partial but progressive migration is no longer manifested, a phenomenon which is evident in reimplantations with cemented cups without the ring.

A unique molecular regulatory mechanism or final common molecular pathway mediating the autonomic dysfunction and several pathobiologic sequelae of spinal cord injury (SCI) in humans has not been delineated. Although seemingly disparate in etiopathogenesis, much of the pathology caused by traumatic disruption of the spinal cord may be attributable to the pleiotropism demonstrated by a unique family of endogenous bioactive molecules, the interleukins. To begin testing this hypothesis, we examined the sera of patients with chronic SCI for elevations in interleukin 1 beta (IL-1 beta) and interleukin 2 receptor (IL-2R) and compared them to a control population of able-bodied subjects. In comparison to control subjects, a statistically significant increase in IL-2R was observed in patients with cervical spinal myelopathy. Elevated levels of IL-2R were not seen in paraplegic patients. Significant differences between the means and variances of serum IL-1 beta could not be detected among the study groups. We conclude that the sera of quadriplegic patients with chronic SCI contain elevated levels of IL-2R and suggest that the elevated levels of IL-2R may be of diagnostic, prognostic, and therapeutic importance.

Patients with spinal cord injury (SCI) have a high incidence of anemia. Intact erythropoietin (EPO) production is essential to the maintenance of erythrocyte mass and prevention and correction of anemia. However, the effect of chronic SCI on EPO production remains unclear. We measured plasma EPO concentration in 83 men with longstanding SCI and a group of normal able-bodied individuals. The SCI patients showed a significant reduction in hematocrit, a high prevalence of anemia, and an increased plasma EPO concentration. Active smokers showed a significantly higher hematocrit and lower EPO concentration than nonsmokers. No significant difference was found in hematocrit or EPO between individuals with paraplegia and those with quadriplegia. A negative correlation was found between EPO and hematocrit in SCI patients lacking significant lung disease. Thus, in the absence of renal insufficiency, EPO response to anemia is qualitatively preserved in SCI patients and is largely independent of the level of injury.

Serum concentration-time course profiles, serum protein binding, and disposition parameters of lorazepam (LRZ), a benzodiazepine with sedative-hypnotic, anxiolytic, and anti-seizure properties, were studied as part of a systematic effort to define population-specific pharmacokinetic behavior in humans with chronic spinal cord injury (SCI). Twenty-four healthy subjects (nine tetraplegic, six paraplegic, nine able-bodied) were given an IV bolus of 2.0 mg of LRZ. Noncompartmental estimation of pharmacokinetic parameters disclosed a 37% decrease in the total systemic clearance (CL) of LRZ in tetraplegic patients. Altered LRZ clearance was observed independently of significant changes in volume of distribution or serum protein binding. The early elimination of LRZ (0-10 hr) was characterized by wide fluctuations in serum concentration suggestive of impaired enterohepatic circulation and could be distinguished from LRZ elimination observed in able-bodied subjects. We conclude that decreased systemic CL and the altered terminal elimination profile of LRZ are attributable to the pathophysiology of SCI.

While changes in the disposition kinetics of aminoglycoside antibiotics have been observed in patients with spinal cord injury (SCI), the extent of binding of aminoglycoside antibiotics to serum protein has not been studied as a potential etiology. Eighty-six serum samples were obtained from 26 volunteers (9 paraplegic, 10 tetraplegic, 7 able-bodied controls) to determine the extent of amikacin binding to serum protein. Free (unbound) amikacin obtained from an ultrafiltrate of serum and total serum amikacin were quantitated over a range of serum concentrations (range 1.37 micrograms/mL to 73.99 micrograms/mL). There was no statistically significant difference demonstrated between mean amikacin serum protein binding in patients with SCI (mean +/- SD, 17.63% +/- 7.22%) and in able-bodied controls (18.03% +/- 3.64%). The percent serum protein binding of amikacin did not covary with total amikacin concentration, and linear regression of free versus total serum amikacin concentrations was expressed by the equation, y = 0.803 x + 0.350, r = 0.979. We conclude that changes in the pharmacokinetic behavior of amikacin in patients with SCI are not attributable to alterations in serum protein binding.

The absolute bioavailability of oral theophylline in five tetraplegic, five paraplegic and three control (intact neuraxes) subjects was studied. All were healthy nonobese males between 20 and 60 years of age, with normal renal and hepatic function. More than 1 year had elapsed from the date of injury in all of the patients with spinal cord injury. None of the study subjects was taking medications known to interfere with theophylline metabolism or the analytic methodology. Each received theophylline in an equivalent amount orally, and by intravenous infusion on 2 occasions separated by not less than 2 weeks. The time course of serum theophylline concentration was followed for up to 24 hours and the area under each oral and intravenous curve extrapolated to infinity (AUC male infinity) was compared using a linear, least-squares, best-fit BASIC program (ESTRIP). A statistically significant difference between means and variances of the absolute bioavailability of oral theophylline, AUCoral male infinity/AUCIV male infinity, (AUCratio +/- SD) was demonstrated in the tetraplegic subjects who showed decreased bioavailability (AUCratio = 0.67 +/- 0.04, range 0.63-0.73) as compared to the paraplegic (AUCratio = 0.95 +/- 0.09, range 0.84-1.08) and control subjects (AUCratio = 0.90 +/- 0.12, range 0.78-1.02). A decrease in the bioavailability of oral theophylline in tetraplegic subjects has not previously been described and may be caused by impaired gastric emptying, which frequently characterizes high myelopathy. Diminished bioavailability could result in underestimation of loading and maintenance doses in tetraplegic humans.

The rate and completeness of absorption of gentamicin from muscle (healthy and paralyzed) and gentamicin disposition kinetics following a single intravenous infusion were studied in nonobese, healthy male volunteers with functionally complete, chronic (greater than one year duration) spinal cord injury (SCI) and in able-bodied controls. Pharmacokinetic parameters were derived using compartmental and model-independent analyses. The absolute bioavailability of gentamicin was complete and did not differ from control values using both model-independent (LAGRAN) and model-dependent (ADAPT) analyses. The rate of gentamicin absorption in patients with SCI was, however, significantly slower, with a mean absorption time of 2.55 h compared with 0.96 h in able-bodied controls (p less than or equal to 0.05). Mean volume of distribution steady-state (Vssd) of gentamicin was demonstrated to be 33-47 percent greater in spinal cord injury than in controls (p less than 0.05). We conclude that the absorption of gentamicin from paralyzed muscle is significantly impaired, and in conjunction with an increase in Vssd results in delayed, decreased peak serum levels in patients with SCI.

Although spinal cord injury is a catastrophic affliction with numerous victims and a variety of physiological manifestations, the associated disarray in physiology has yet to be systematically or comprehensively studied as a probable cause for altered pharmacokinetics. A significant increase in the volume of distribution of drugs such as the aminoglycosides (gentamicin, amikacin, tobramycin), which are highly distributed into the extracellular fluid space and minimally biotransformed, may be anticipated in patients with chronic spinal cord injury. Changes in total body clearance have also been observed for some of these medications. The influence of the pathophysiology of spinal cord injury on gastrointestinal motility appears to be reflected in an impairment in the bioavailability of drugs [theophylline, paracetamol (acetaminophen), doxycycline] which are passively absorbed and which require an intact postprandial gastric emptying to ensure efficient absorption. For theophylline, the impairment in gastrointestinal absorption appears to be directly proportional to both the magnitude of the impairment in gastric emptying and to the neurological level of the injury. Metoclopramide, a gastrointestinal prokinetic drug, has been shown to be extremely effective in normalising the impaired postprandial gastric emptying that characterises spinal cord injury. The systemic absorption of 2 antibiotics (gentamicin and cefotiam) injected into paralysed muscle is also impaired in patients with spinal cord injury, suggesting that a decrease in therapeutic efficacy attributable to this mode of administration may be anticipated. Despite the multiplicity of drugs commonly prescribed for patients with this injury, little is known about the influence of this illness on either bioavailability or postabsorptive pharmacokinetics. For drugs which are biotransformed and which have a relatively small volume of distribution (theophylline, lorazepam, ranitidine), single-dose intravenous pharmacokinetic profiles in patients with spinal cord injury are indistinguishable from the drug disposition profiles characteristic of healthy control populations. It may be inferred, then that the influence of the pathophysiology of spinal cord injury on drug disposition is greatest on those drugs which are the least biotransformed and most likely to be distributed into the increased extracellular fluid volume which is characteristic of patients with this disability.(ABSTRACT TRUNCATED AT 400 WORDS)

In a partial, two-way crossover study of gastric emptying (GE) in spinal cord injury (SCI), fasted, healthy, unmedicated male volunteers were given a 99mTc-labeled liquid meal on two occasions. Metoclopramide (10 mg) was administered intravenously to each subject before the second evaluation of GE. We used single and multiexponential models with linear and nonlinear least-squares regression techniques to study the time-course of the disappearance of 99mTc from the stomach. The GE pattern in all subjects was most accurately characterized by nonlinear analysis (NONLIN) and consisted of two components, an initial adynamic phase and a phase of rapid emptying. The GE t1/2 of a liquid meal decreased from 106.6 +/- 58.3 min (mean +/- SD) in all SCI subjects (quadriplegic plus paraplegic) prior to treatment to 21.6 +/- 8.2 min after the intravenous administration of metoclopramide (p less than 0.006). Significant correlations between GE t1/2 and injury duration (yr) or level of spinal injury were observed. Impaired gastric emptying in SCI can be pharmacologically modified by metoclopramide to resemble a normal gastric emptying profile. Metoclopramide-altered gastric emptying in SCI may be expected to result in changes in the therapeutic efficacy of orally administered drugs when drug absorption is dependent on gastric motility or emptying efficiency.

The influence of chronic (greater than 1 yr duration) spinal cord injury (SCI) on the disposition of amikacin was studied in seven healthy subjects with SCI (five paraplegic, two tetraplegic) and seven able-bodied controls (intact neuraxes). The time course of amikacin serum concentration after a 30-minute infusion (7.5 mg/kg) was followed for up to 8.5 hours using fluorescence polarization immunoassay. Pharmacokinetic values were estimated by a noncompartmental analysis (NC). Amikacin steady-state volume of distribution (Vss) was increased to 0.20 +/- 0.04 l/kg (mean +/- SD) as compared to 0.17 +/- 0.02 l/kg in able-bodied controls (p 0.03), and its mean terminal elimination half-life in patients with SCI was prolonged by 0.64 hours over the control value of 2.11 +/- 0.27 hours (p 0.01). The NC estimated mean residence time (MRT) in patients with SCI (3.65 +/- 0.75 hrs) was 0.89 hours longer than that observed in controls (p 0.03). Our data suggest that the Vss, half-life, and MRT of amikacin are increased in persons with chronic SCI. As a result, amikacin dosing regimens developed in able-bodied humans may demonstrate diminished efficacy when extrapolated uncritically to these patients.