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.

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.

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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.

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)

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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 ≤ 0.05). Mean volume of distribution steady-state (Vdss) of gentamicin was demonstrated to be 33–47 percent greater in spinal cord injury than in controls (p < 0.05). We conclude that the absorption of gentamicin from paralyzed muscle is significantly impaired, and in conjunction with an increase in Vdss results in delayed, decreased peak serum levels in patients with SCI.

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