Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation.

Estradiol affects hippocampal-dependent spatial memory and underlying structural and electrical synaptic plasticity in female mice and rats. Using estrogen receptor (ER) alpha and beta knockout mice and wild-type littermates, we investigated the role of ERs in estradiol effects on multiple pathways important for hippocampal plasticity and learning. Six hours of estradiol administration increased immunoreactivity for phosphorylated Akt throughout the hippocampal formation, whereas 48 h of estradiol increased immunoreactivity for phosphorylated TrkB receptor. Estradiol effects on phosphorylated Akt and TrkB immunoreactivities were abolished in ER alpha and ER beta knockout mice. Estradiol also had distinct effects on immunoreactivity for post-synaptic density 95 (PSD-95) and brain derived-neurotrophic factor (BDNF) mRNA in ER alpha and beta knockout mice. Thus, estradiol acts through both ERs alpha and beta in several subregions of the hippocampal formation. The different effects of estradiol at 6 and 48 h indicate that several mechanisms of estrogen receptor signaling contribute to this female hormone's influence on hippocampal synaptic plasticity. By further delineating these mechanisms, we will better understand and predict the effects of endogenous and exogenous ovarian steroids on mood, cognition, and other hippocampal-dependent behaviors.

A randomized trial of local anesthesia with intravenous sedation vs general anesthesia for the vaginal correction of pelvic organ prolapse.

The purpose of this study is to compare the feasibility of local anesthesia with IV sedation versus general anesthesia for vaginal correction of pelvic organ prolapse. Patients with pelvic organ prolapse who were scheduled for an anterior or posterior colporrhaphy, or an obliterative procedure, and who did not have a contraindication or preference to type of anesthesia were randomized to one of the two anesthesia groups. Nineteen patients were randomized to the general group and 21 patients were randomized to the local group. Mean operating room, anesthesia, and surgical time were similar in each group, and 10 patients in the local group bypassed the recovery room. Requests and doses of antiemetics, postoperative verbal numerical pain scores and length of hospital stay were similar between the two groups. Mean recovery room and total hospital costs were significantly lower in the local group. Local anesthesia with IV sedation is a feasible alternative for vaginal surgery to correct pelvic organ prolapse.

Optimal drug therapy and therapeutic drug monitoring after spinal cord injury: a population-specific approach.

Study of the clinical pharmacology of SCI has revealed population-specific patterns of drug metabolism and disposition. PD/PK profiles reflect the changed physiology associated with SCI and correlate well with the neurologic or anatomic level and the magnitude and completeness of the injury. The greatest value of SCI PK/PD profiles lies in their use in developing criteria and strategies for the optimal prescribing of drugs and in therapeutic drug monitoring. Patients with SCI, acute or long-standing, comprise a therapeutically unique and distinct population. Rational, efficacious, and cost-effective approaches to drug development and pharmacotherapy in spinal cord-injured patients can only come about when population-specific PK/PD behavior is incorporated early into the drug development process and used to develop safe, effective therapeutic guidelines.

Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury.

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.

Safety and efficacy of 4-aminopyridine in humans with spinal cord injury: a long-term, controlled trial.

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.

4-Aminopyridine alters gait characteristics and enhances locomotion in spinal cord injured humans.

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.

Heart rate variability is altered following spinal cord injury.

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.

Randomized double-blind crossover trial of fampridine-SR (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury.

A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of fampridine-SR over placebo on patient satisfaction (McNemar's test, p2 < 0.05) and quality of life scores (p2 < 0.01). Sensory scores (p1 < 0.01), including both pin prick (p1 = 0.059) and light touch (p1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p1 < 0.01) all yielded evidence of benefit of fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p2 < 0.05) reduced when patients received fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30% of patients reported a wish to continue to use fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of fampridine-SR in SCI patients.

Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases.

Preclinical trials of intravenously administered 4-Aminopyridine (4-AP) have demonstrated transient improvements in neurological function in patients with longstanding spinal cord injury (SCI). The present report describes three patients with SCI who responded favourably in preclinical trials and who were subsequently administered oral (capsule) 4-AP (10 mg b.i.d. or t.i.d.) over a 4 month interval. The three patients (two male: 1 female) all had incomplete tetraplegia (ASIA levels C and D) with the neurological level of the lesion between C5-C7. Following the administration of 4-AP the patients demonstrated marked and sustained reductions in upper (n = 1) or lower extremity (n = 2) spasticity. Other clinical benefits of 4-AP were reduced pain (n = 1), restored muscle strength (n = 3), improved sensation (n = 2), voluntary control of bowel function (n = 1), and sustained penile tumescence (n = 2). The patients exhibited improved hand function (n = 1), enhanced mobility in transfers and gait (n = 2), with improved energy and endurance. Only trivial side effects (transient light-headedness) were observed. In one case, the enhanced neurological function allowed the patient to stand with support for the first time post injury (16 years). The time course of therapeutic response to the initial dose matched the pharmacokinetic elimination profile derived from serum and urine analysis. There was no evidence of renal or hepatic toxicity with prolonged use. These results indicate a therapeutic benefit of oral 4-Aminopyridine in the management of various neurological deficits in a select group of SCI patients.

Methylprednisolone disposition kinetics in patients with acute spinal cord injury.

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.

4-Aminopyridine improves pulmonary function in quadriplegic humans with longstanding spinal cord injury.

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.

Circulating levels of IL-2R, ICAM-1, and IL-6 in spinal cord injuries.

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.

Reversal of erythema multiforme major with cyclophosphamide and prednisone.

OBJECTIVE: To report a case of erythema multiforme (EM) major treated with cyclophosphamide and prednisone. SETTING: General medicine and dermatology consult services, Department of Veterans Affairs Medical Center. CASE SUMMARY: A 44-year-old man with C4-C5 quadriplegia developed a skin reaction characterized by a painful, generalized maculopapular rash, bullae, ulceronecrotic lesions, and mucosal and epidermal sloughing after taking trimethoprim/sulfamethoxazole. The patient was treated with intravenous cyclophosphamide 150 mg infused over 1 hour every 24 hours and oral prednisone 15 mg every 6 hours. After two doses of cyclophosphamide, formation of bullae and epidermal sloughing had ceased, and the erythema was markedly diminished. Cyclophosphamide was discontinued before the third dose because of evolving leukopenia. Prednisone therapy was continued until the patient was discharged on hospital day 5, at which time the dosage was tapered. DISCUSSION: Cyclophosphamide has been used extensively for other dermatologic reactions. Relief of pain and regression of the lesions in our patient occurred more quickly than anticipated. CONCLUSIONS: Treatment of EM major with cyclophosphamide combined with prednisone appeared to be highly successful in this patient. Cyclophosphamide may be an effective, empiric initial treatment in reversing EM major.

Metoclopramide increases the bioavailability of dantrolene in spinal cord injury.

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.

Bioelectrical impedance analysis as an assessment of diuresis in congestive heart failure.

OBJECTIVE: To compare changes in bioimpedance parameters and calculated total body water (TBW) with conventional measurements used to assess the efficacy of diuretic therapy in the treatment of heart failure. SETTING: A Veterans Affairs tertiary care, teaching hospital. SUBJECTS: Twelve patients with New York Heart Association (NYHA) class III congestive heart failure (CHF). DESIGN: Prospective, consecutive sample, cohort, open label. INTERVENTIONS: Parenterally administered furosemide; clinically dictated, outcome-oriented, adjunctive therapy of CHF. OUTCOMES: Bioelectrical impedance analysis (BIA) parameters, measured volume of diuresis and changes in body weight, defined clinical endpoints (NYHA criteria). RESULTS: Three days of diuretic therapy with furosemide (oral and/or intravenous) for CHF was associated with a measured weight loss of 4.1 +/- 0.6 kg and statistically significant increases in resistance and reactance of 20.8% +/- 2.7% and 22.7% +/- 6.1%, respectively (p < 0.005). Calculated TBW using BIA parameters and standard equations decreased on average by 6.1 +/- 0.6 L or 11.2% +/- 1.1% (p < 0.001). A significant inverse correlation was observed between change in measured body weight and total body reactance (p = 0.02). CONCLUSIONS: Single-frequency BIA appears to have limited clinical usefulness as a method of assessing diuretic therapy in the management of CHF. Its greatest usefulness appears to lie in the assessment of serial changes in individual patients and patient populations that are physiologically or metabolically homogeneous. Further studies are needed to establish the validity of BIA in patients with decompensated CHF.

Gastric emptying is impaired in patients with spinal cord injury.

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.

Vitamin D, parathormone, and calcitonin profiles in persons with long-standing spinal cord injury.

Rapid immobilization after acute spinal cord injury (SCI) leads to increased bone resorption, net calcium efflux from the bone, hypercalciuria, depressed parathormone (PTH) and increased calcitonin release. However, the effects, if any, of long-standing SCI on calcium regulatory system is not well understood. We measured plasma concentrations of 25 hydroxy (OH) vitamin D, 1,25(OH)2 vitamin D (calcitriol), intact PTH molecule, calcitonin, ionized calcium [Ca++] and phosphorus in 40 clinically stable men with long-standing SCI of 3-year to 50-year duration (22 persons with paraplegia and 18 persons with quadriplegia). The results were compared with those obtained in 14 able-bodied control men. Plasma PTH concentration in the SCI group was significantly lower than that found in the able-bodied controls despite virtually identical concentrations of ionized calcium. Likewise, plasma calcitriol concentration in the SCI group was significantly lower than the value found in the able-bodied control group and lower in persons with quadriplegia than in those with paraplegia. In contrast, plasma calcitonin concentration in the quadriplegic group was significantly higher than that in persons with paraplegia and insignificantly higher than that in the control group. No significant difference was noted in serum ionized calcium between the study groups. PTH and calcitriol levels were positively related to one another (r = 0.35, p < .01) and negatively related to the level of injury (r = -0.43, p < .002 and r = -0.54, p < .001, respectively). In conclusion, long-standing SCI is associated with significant depression of calcitriol and PTH concentrations despite normal ionized calcium concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of population pharmacokinetic models for gentamicin in spinal cord-injured and able-bodied patients.

Population pharmacokinetic models for gentamicin were developed by using data obtained from 29 spinal cord-injured patients and 11 able-bodied control patients. With a one-compartment model, the population parameters were clearance (CL), volume of distribution (V), and their associated variances. Parameter estimates were found by using the computer program NPEM and by the standard two-stage (STS) method. NPEM uses a nonparametric approach incorporating the expectation maximization algorithm to evaluate a joint probability density function at 900 intersections over a bivariate grid. In contrast, the STS method requires conventional assumptions of normality for the underlying distributions. For NPEM, the mean CL was 97.6 ml/h/kg of body weight (coefficient of variation, 33.0% in the spinal cord-injured patients and 67.8 ml/h/kg +/- 28.2% in the able-bodied patients; the mean V was 0.31 liter/kg +/- 32.3% in the spinal cord-injured patients and 0.23 liter/kg +/- 15.8% in the able-bodied patients. For STS, the mean CL was 101.0 ml/h/kg +/- 37.5% in the spinal cord-injured patients and 65.0 ml/h/kg +/- 33.8% in the able-bodied patients; the mean V was 0.29 liter/kg +/- 34.0% in the spinal cord-injured patients and 0.21 liter/kg +/- 21.0% in the able-bodied patients. Although the means and variances found by NPEM and the STS method were similar, the NPEM analysis revealed that the distributions of CL and V, even after they were linked to weight, were positively skewed and kurtotic. The cumulative distribution functions for CL (P < 0.001) and V (P < 0.001) in spinal cord-injured patients were different from those in able-bodied patients. Unique population models are required for the initial dosage selection for spinal cord-injured patients. Future approaches for developing population models should allow the linkage of structural parameters to multiple patient covariates.

Circulating levels of soluble interleukin 2 receptors are elevated in the sera of humans with spinal cord injury.

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.