High doses of 4-aminopyridine improve functionality in chronic complete spinal cord injury patients with MRI evidence of cord continuity.

BACKGROUND AND AIMS: Many patients with complete spinal cord injury (SCI) exhibit demyelinated and poorly myelinated nerve fibers traversing the lesion site. Conventional doses of 4-aminopyridine (4-AP, 30 mg/day) have shown to provide no or minor functional improvement in these patients. We undertook this study to test the functional effect of high doses of 4-AP on patients with chronic complete SCI with cord continuity at the site of injury demonstrated by magnetic resonance imaging. METHODS: Fourteen patients were included in a double-blind, randomized, placebo-controlled trial followed by an open label long-term follow-up. Initially, patients received 4-AP or placebo orally, with 4-AP being increased gradually (5 mg/week) to reach 30 mg/day. For long-term treatment, 4-AP was increased 10 mg periodically according to negative electroencephalogram and blood test abnormalities and minor adverse reactions. Pre-treatment, 12 and 24 weeks of the controlled trial, and 6 and 12 months of open trial evaluations, or with the highest doses reached were obtained. RESULTS: Three of 12 patients were able to walk with the assistance of orthopedic devices, 1/12 became incomplete (AIS B), 7/12 improved their somatosensory evoked potentials, 5/12 had sensation and control of bladder and anal sphincters, and 4/9 male patients had psychogenic erection. CONCLUSIONS: Positive changes were seen mainly in patients with cyst (4/5) or atrophy (3/5) of the injury site. Two patients withdrew from the study: one had seizures and one had intolerant adverse reactions. We conclude that high doses of 4-AP in the studied population produced several functional benefits not observed using lower doses.

Efficacy and safety of 4-aminopyridine in patients with long-term spinal cord injury: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To study the efficacy and safety of 4-aminopyridine (4-AP), and to document sensorimotor changes after discontinuation of the drug in patients with long-term spinal cord injury. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Clinical research unit. PATIENTS: Twenty-seven patients with long-term spinal cord injury. INTERVENTION: Patients were randomized to receive either oral 4-AP 5 mg/day, which was increased by 5 mg/week to a maximum dosage of 30 mg/day, or placebo for 12 weeks. They switched to the opposite treatment for the next 12 weeks. MEASUREMENTS AND MAIN RESULTS: Twenty-five patients finished the study. The results from the first 12 weeks were used to test efficacy. Positive gains in motor function, sensation, and independence occurred more frequently in patients receiving 4-AP (69%) than those receiving placebo (46%). Significant functional improvement was also noted in those treated with 4-AP (chi2, p=0.042). When each evaluation scale was considered separately, significant improvement was seen only in motor function (4-AP 92% vs placebo 46%, Fisher exact test, p=0.03). Persistent effects of the drug were assessed at week 24 in the group that initially received 4-AP. A persistent, significant 4-AP effect was observed in evaluations of sensation and independence (67% and 83% of patients, respectively; Wilcoxon signed rank test, p=0.032 and 0.042, respectively). Fourteen (56%) patients had 26 adverse reactions. One moderate adverse reaction--posterior tibial artery vasospasm--and 25 mild adverse reactions, such as dry mouth, dizziness, nausea, gastritis, oral and peripheral paresthesia, resolved adequately. Six (24%) patients experienced transitory alterations of enzyme levels (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and creatine kinase) and thrombocytopenia. CONCLUSION: Patients who received 4-AP showed significant improvement in motor function, and a persistent effect on sensation and independent function occurred. The drug is safe; however, after starting 4-AP therapy, patients must be carefully monitored for the possible occurrence of peripheral vasospasm.

Relationship of insulin resistance and overweight with cortisol and dehydroepiandrosterone-sulfate levels.

BACKGROUND: Our objective was to assess the relationship of hormones such as cortisol and dehydroepiandrosterone-sulfate (DHEA-S) with insulin resistance and overweight. METHODS: We designed and conducted a cross-sectional, observational survey consisting of home visits within a previously defined area of Mexico City. The study included 303 apparently healthy volunteers from a middle-class socioeconomic urban community. We measured glucose, cholesterol, triglycerides, insulin, cortisol, and DHEA-S. Insulin resistance (IR) was defined as belonging to the first quartile of fasting glucose/insulin ratio (G/IR) distribution or fourth quartile of IR (HOMA). Overweight was defined as body mass index (BMI) > or =25 kg/m(2). RESULTS: To predict IR in women < or =35 years of age, principal component analysis (PCA) disclosed three components: 1) cholesterol, BMI, and diastolic blood pressure (DBP); 2) cholesterol, triglycerides, and cortisol, and 3) dehydroepiandrosterone-sulfate [DHEA-S]. Solely the latter (DHEA-S) was significantly associated with IR (odds ratio [OR] = 1.80, confidence interval 95% [CI 95%] 1.11-2.91, p = 0.015). For men < or =35 years of age, there were two components: 1) cholesterol, triglycerides, BMI, and DBP, and 2) DHEA-S, cholesterol, and cortisol. Component 1 was significantly associated with IR (OR = 5.65; CI 95% 1.62-19.65, p = 0.006). To predict overweight in women >35 years of age, there were three components, including 1) cholesterol and triglycerides, 2) cortisol, and 3) DHEA-S and G/IR. Component 2 was significantly associated with overweight (OR = 0.38, CI 95% 0.23-0.64, p = 0.000). CONCLUSIONS: In women < or =35 years of age, high DHEA-S levels were associated with insulin resistance, which suggests that in young women DHEA-S exerts anti-estrogenic action, perhaps caused by its competitive binding with the estrogen receptor. Additionally, in women >35 years of age, low cortisol levels were associated with overweight. These associations were not identified for the male subgroup.