Derivation of an occupational exposure limit for inorganic borates using a weight of evidence approach.

Inorganic borates are encountered in many settings worldwide, spurring international efforts to develop exposure guidance (US EPA, 2004; WHO, 2009; ATSDR, 2010) and occupational exposure limits (OEL) (ACGIH, 2005; MAK, 2011). We derived an updated OEL to reflect new data and current international risk assessment frameworks. We assessed toxicity and epidemiology data on inorganic borates to identify relevant adverse effects. International risk assessment frameworks (IPCS, 2005, 2007) were used to evaluate endpoint candidates: reproductive toxicity, developmental toxicity, and sensory irritation. For each endpoint, a preliminary OEL was derived and adjusted based on consideration of toxicokinetics, toxicodynamics, and other uncertainties. Selection of the endpoint point of departures (PODs) is supported by dose-response modeling. Developmental toxicity was the most sensitive systemic effect. An OEL of 1.6mgB/m(3) was estimated for this effect based on a POD of 63mgB/m(3) with an uncertainty factor (UF) of 40. Sensory irritation was considered to be the most sensitive effect for the portal of entry. An OEL of 1.4mgB/m(3) was estimated for this effect based on the identified POD and an UF of 1. An OEL of 1.4mgB/m(3) as an 8-h time-weighted average (TWA) is recommended.

Human health risks from mercury exposure from broken compact fluorescent lamps (CFLs).

Human health risk to infants/toddlers and adults was evaluated based on two exposure scenarios from compact fluorescent lamp (CFL) breakage; first in a room with no ventilation and no clean-up, and second in a room with adequate ventilation and clean-up. Concentration data from multiple exposure scenarios tested in a study by Stahler et al. (2008) were compared to human toxicity benchmarks to calculate hazard quotients. For the no clean-up scenario, hazard quotients were generally less than 1, suggesting an unlikely health risk. When the room was ventilated and the broken CFL was cleaned-up, mercury concentrations were generally lower. A review of release scenarios, along with duration-adjusted toxicity benchmarks, indicated that few releases produced levels of concern, but some scenarios resulted in exceedance of risk targets and require further study. Uncertainties in this screening characterization include assumptions about room size, ventilation, age of lamp, the distribution of mercury in the room, and also the choice of the toxicity benchmarks used to develop the hazard quotients.

International spinal cord injury musculoskeletal basic data set.

OBJECTIVES: To develop an International Spinal Cord Injury (SCI) Musculoskeletal Basic Data Set as part of the International SCI Data Sets to facilitate consistent collection and reporting of basic musculoskeletal findings in the SCI population. SETTING: International. METHODS: A first draft of an SCI Musculoskeletal Basic Data Set was developed by an international working group. This was reviewed by many different organizations, societies and individuals over 9 months. Revised versions were created successively. RESULTS: The final version of the International SCI Musculoskeletal Basic Data Set contains questions on neuro-musculoskeletal history before spinal cord lesion; presence of spasticity/spasms; treatment for spasticity within the last 4 weeks; fracture(s) since the spinal cord lesion; heterotopic ossification; contracture; the location of degenerative neuromuscular and skeletal changes due to overuse after SCI; SCI-related neuromuscular scoliosis; the method(s) used to determine the presence of neuromuscular scoliosis; surgical treatment of the scoliosis; other musculoskeletal problems; if any of the musculoskeletal challenges above interfere with activities of daily living. Instructions for data collection and the data collection form are freely available on the International Spinal Cord Society (ISCoS) website (www.iscos.org.uk). CONCLUSION: The International SCI Musculoskeletal Basic Data Set will facilitate consistent collection and reporting of basic musculoskeletal findings in the SCI population.

Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.

STUDY DESIGN: Randomized, double-blind, placebo-controlled, two-period crossover. OBJECTIVES: To evaluate the efficacy and safety of arbaclofen placarbil (AP) in patients with spasticity secondary to spinal cord injury (SCI). SETTING: United States and Canada. METHODS: Patients received extended-release AP tablets 10, 20 or 30 mg every 12 h in one of two AP/placebo sequences, with 26 days of each treatment. The primary analysis compared Ashworth scale assessments of muscle tone between AP and placebo for the muscle group with maximum baseline Ashworth score. Secondary endpoints included a patient-rated Severity of Spasticity Scale. RESULTS: In the primary analysis, AP significantly improved Ashworth scores compared with placebo over the dosing interval: least-squares mean reduction versus placebo was 0.60 for AP 20 mg (P=0.0059) and 0.88 for AP 30 mg (P=0.0007). The difference was significant for the pre-morning dose time point, 12 h after the prior evening dose, indicating that efficacy was maintained throughout the dosing interval. Treatment differences for AP 10 mg versus placebo were not significant. Severity of Spasticity ratings were significantly reduced for the combined 20/30-mg group versus placebo (P=0.018). No statistically significant differences between AP and placebo were observed for muscle strength. AP-related AEs were generally mild to moderate in intensity, and none led to early withdrawal or were serious. CONCLUSION: AP was well tolerated at all investigated dosages and, when administered at doses of 20 or 30 mg twice daily, was efficacious in reducing spasticity due to SCI.

Relationship of the antispasticity effect of tizanidine to plasma concentration in patients with multiple sclerosis.

BACKGROUND: Spasticity is a serious problem in multiple sclerosis (MS) and many patients do not achieve a satisfactory response to currently available oral antispasticity drugs. Tizanidine hydrochloride, an alpha 2-noradrenergic agonist, has been shown to have an antispasticity effect in single center trials of patients with MS. OBJECTIVE: To compare plasma concentrations of tizanidine with objective measures of muscle tone in patients with MS with moderate to severe spasticity. SETTING: Ten centers, all tertiary referral centers for the specialized treatment of patients with MS, in the United States and Canada. DESIGN: A randomized, double-blind, placebo-controlled, dose-response study of tizanidine hydrochloride (8 or 16 mg). PATIENTS: One hundred forty-two patients with spastic MS who were not taking any interfering medication, such as an antispasticity drug or other alpha-noradrenergic agonist, entered the trial. RESULTS: Tizanidine treatment reduced muscle tone significantly, as shown by improved Ashworth scores and increased knee swing amplitude recorded by the pendulum test, both of which correlated significantly with plasma concentration. Placebo had no significant effect on muscle tone. Dizziness, drowsiness, dry mouth, and fatigue were reported most often in the group treated with tizanidine at peak plasma concentration. CONCLUSIONS: Tizanidine reduces spasticity in MS, and both therapeutic effects and side effects are related to the plasma drug levels.

Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. North American Tizanidine Study Group.

Tizanidine, an imidazoline that acts as an agonist at alpha 2-adrenergic receptors, has been shown to be effective in reducing spasticity caused by MS. This multicenter study (14 sites) assessed the efficacy and safety of oral tizanidine in patients who had spinal cord injury of > 12 months' duration. Of the 124 patients admitted to the study, 78 completed it. Tizanidine was titrated to an optimized dosage in each patient to a maximum of 36 mg/d. Muscle tone, assessed by Ashworth score, was significantly reduced (p = 0.0001) by tizanidine treatment in comparison with placebo. Video motion analysis of the pendulum test showed improvement in the tizanidine-treated patients vs placebo (p = 0.04) and showed a significant correlation with the Ashworth score (p < 0.001). No significant alterations in muscle strength or vital signs were noted in either treatment group. The most common adverse events during tizanidine treatment were somnolence, xerostomia, and fatigue. It was concluded that, overall, tizanidine is effective in reducing spasticity in patients with spinal cord injury.

Neuroendocrine and behavioral effects of intrathecal capsaicin in adult female rats.

Neural feedback from the gonads and the reproductive tract has an integral role in normal reproductive function in female rats. To further assess the role of sensory feedback in neuroendocrine control, the effects of an intrathecal injection of the neurotoxin, capsaicin (100-125 micrograms) into the lumbosacral region of the spinal cord on reproductive function was tested in female rats. In addition, the effects of capsaicin on the response to noxious heat and pressure were tested. Intrathecal capsaicin had no effect on estrous cycles, ovarian compensatory hypertrophy or female sexual behavior. However, capsaicin treated animals showed a dramatic reduction in fertility, relative to vehicle treated control rats and this was shown to be due to the reduced capacity of vaginal/cervical stimulation to produce pseudopregnancy. Consistent with a selective loss in the effectiveness of cervical stimulation, immobilization produced by vaginal probing was reduced in capsaicin treated rats, but this response slowly recovered across time in some animals. Similarly, the ability of vaginal probing to induce a lordotic response during estrogen treatment was reduced in the capsaicin treated animals. The capsaicin treated animals showed analgesia to noxious heat, as measured by the tail flick test, but showed a normal foot withdrawal in response to pressure. The analgesic effect of vaginal stimulation on noxious pressure was unaltered in the capsaicin treated rats. Finally, the neurotoxic effect of capsaicin was verified in terms of a quantitative reduction in substance P immunoreactivity in the dorsal horns of the lumbosacral region of the spinal cord of capsaicin treated rats, relative to control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrathecal baclofen therapy for adults with spinal spasticity: therapeutic efficacy and effect on hospital admissions.

A prospective trial to demonstrate the efficacy of intrathecal baclofen therapy by implanted pump for adults with spasticity due to spinal cord injury or multiple sclerosis was initiated in our hospital. Of the 140 patients assessed, 7 met the following criteria for inclusion in the study: a modified Ashworth score > 3, a spasm frequency score > 2, and an inadequate response to oral anti-spasticity drugs, (i.e., baclofen, clonidine and cyproheptadine). All patients responded to intrathecal bolus injection of baclofen in the double blind, placebo-controlled screening phase (mean bolus dose = 42.8 micrograms). Programmable Medtronic pumps were implanted in 4 patients while 3 patients received non-programmable Infusaid pumps. Post-implantation, a marked decrease in spasticity occurred with a significant reduction of the Ashworth score (mean = 1.8, p < .005), a reduced spasm score (mean = 0.8, p < .005), and an improved leg swing in the pendulum test. These effects were maintained during a follow-up of 24-41 months (average infusion dose = 218.7 micrograms/day). The gross cost-savings due to reduced hospitalizations related to spasticity was calculated by comparing the cost for the two year period before pump implantation to the same period after treatment for 6 of the 7 patients. The cost of in-hospital implantation as well as the cost of the pumps were deducted from the gross savings. There was a net cost-saving of $153,120. Our findings agree with the reported efficacy and safety of intrathecal baclofen treatment, and illustrate the cost-effectiveness of this treatment.

Alpha adrenergic and serotonergic agents in the treatment of spastic hypertonia.

In the treatment of patients with problematic spasticity, it is important to consider the following steps: 1. Establish the functional impact of the spasticity. 2. Identify the functional goal to be achieved by treatment. 3. Eliminate any remediable spasticity aggravating factors. 4. Evaluate the effects of previous antispasticity treatments. 5. Consider nonpharmacologic and pharmacologic treatments. 6. Initiate therapy with a low dosage, and titrate judiciously. 7. Stop the titration when functional goal is achieved. 8. If goal is not achieved or if side effects are intolerable, consider a second medication.

Intrathecal drug therapy.

The direct application of drugs for non-hospitalized patients became a practical therapeutic modality with the advent of implantable drug delivery devices, or "pumps". This article describes the use of pumps for the intrathecal infusion of baclofen, morphine and clonidine.

Analgesics. Opioids, adjuvants, and others.

The purpose of this article is to summarize the main categories of pain-relieving medications. The authors review a number of analgesic preparations and treatments, with special emphasis on advantages, precautions, limitations, and various routes of administration.

Antispasticity medications.

The article illustrates a practical approach to the challenging management of problematic, generalized spasticity. Use of dose titration to achieve symptomatic relief is described. Currently approved pharmaceuticals used as antispasticity agents and muscle relaxants and other medications with antispasticity effects are reviewed.

Urinary and gastrointestinal systems medications.

This article reviews the medical management of the neurogenic bladder and bowel. The drugs discussed specifically affect detrusor instability, detrusor weakness, high urethral pressure, low urethral closure pressure, inflammatory cystitis, and chronic constipation.

Intrathecal drug therapy using the Codman Model 3000 Constant Flow Implantable Infusion Pumps: experience with 17 cases.

OBJECTIVES: The objective of this study was to evaluate the accuracy, reliability, safety, and efficacy of the Codman Model 3000 Constant Flow Implantable Infusion Pump for intrathecal baclofen delivery as a therapeutic option for the treatment of severe spasticity. The distinctive features of this pump include a raised, easily palpable septum, a safety valve protecting the bolus pathway, no programmer needed, and no battery to fail. DESIGN: A total of 17 patients with spinal cord injury, multiple sclerosis, or cerebral palsy were implanted with this pump. The accuracy of the pump and drug treatment efficacy was determined at each visit and adjustments to the dosages were made as required. All the intrathecal drug delivery system complications were reviewed. RESULTS: The expected efficacy was achieved. The accuracy of the implanted pumps ranged from 90-97% (average 94%). There were no complications due to primary pump problems. The complications reported are similar to other implantable infusion devices and include dehiscence of the suture line, pressure ulcer development, formation of seroma, inversion of the pump, baclofen overdose, and catheter failures. CONCLUSION: The Codman Model 3000 Constant Flow Implantable Infusion Pump is an accurate, reliable, and convenient option for patients needing intrathecal baclofen therapy, with complications similar to other available pumps.

A comparison of clonidine, cyproheptadine and baclofen in spastic spinal cord injured patients.

In twenty-five SCI subjects, antispasticity effects of three putative antispasticity agents [clonidine (an alpha-2 noradrenergic agonist), cyproheptadine (a 5-HT2 antagonist) and baclofen (a GABA-B agonist)] were tested in terms of changes in leg tone as graded by the Ashworth scale (AS), in terms of the vibratory inhibition of the H-reflex (VII) and in terms of the ability of the knee to swing passively in the pendulum test as quantified by video motion analysis. When compared to the no drug period, all three drug treatments showed an antispasticity effect on the AS, the VII and the amplitude of the first swing and the relaxation index of the pendulum test, p. < 0001. Surprisingly, cyproheptadine and baclofen produced a greater reduction in the VII than clonidine, p. < 01. The amplitude of the first swing in the pendulum test correlated well with the AS, r = .88, and the antispasticity effects of the drugs produced improvements in both measures, a reduced AS and increased amplitude of knee swing in the pendulum test. Therefore, video motion analysis of the pendulum test is as valid a measure of spasticity as the Ashworth scale and is not limited by subjectivity of the examiner.

Gait analysis of spinal cord injured subjects: effects of injury level and spasticity.

OBJECTIVE: To identify abnormalities in the gait of spinal cord injured (SCI) subjects, particularly in relation to injury level and spasticity. DESIGN: Case-control study comparing the gait of SCI individuals with matched controls. Video-motion analysis was used to collect data on temporal and kinematic variables. Spasticity was assessed using the Ashworth score and pendulum test. Data regarding age, height, weight, mechanism, and level of injury were also collected. SETTING: Spinal cord injury clinic of a tertiary care hospital. PARTICIPANTS: Twenty-seven SCI individuals volunteered to participate in the study. All had retained walking ability (Frankel D) and could ambulate independently for a minimum of 10m with or without walking aids. Individuals with cauda equina injuries were excluded from the study. Age, gender, etiology of injury, and interval since injury were not used as exclusion criteria. Ten age-, sex-, and anthropomorphically matched controls were also recruited. RESULTS: Subjects with thoracic injures demonstrated reduced cadence, forward velocity, and knee angular velocity, whereas lumbar injuries resulted in reduced stride length and ankle velocities. These differences were statistically significant (p < .05). Gait in individuals with cervical injuries was not significantly different. CONCLUSIONS: Kinematic gait analysis is a sensitive means of quantifying gait abnormalities. Spasticity and injury level determine the pattern of abnormality in gait after spinal cord injury.

Dissociated hip and spine demineralization: a specific finding in spinal cord injury.

Bone mineral density of the lumbar spine and right hip was measured with dual x-ray absorptiometry in 14 men with chronic spinal cord injury (SCI). The pattern of demineralization was compared to that observed in 46 men with a variety of endocrine disorders (chronic steroid use seven, chronic neuroleptic use 15, prolactinoma three, hypogonadism six, hyperthyroidism three, idiopathic osteoporosis 12). The SCI patients had significant hip demineralization but normal bone density in the lumbar spine (percent of age-matched normal 86.0 +/- 3.8 for the femoral neck, 101.8 +/- 4.3 for the lumbar spine; t = 3.88, p = 0.002). In contrast, the endocrine disorders were associated with disproportionate lumbar spine demineralization (percent of age-matched normal 97.5 +/- 1.9 for the femoral neck, 81.8 +/- 2.0 for the lumbar spine; t = 8.98, p < 0.000001). We conclude that hip demineralization is a common complication of SCI but that lumbar bone density is well preserved. This pattern of highly selective bone loss from the hip appears to be unique compared to other endocrine causes of osteoporosis.

Substance P-induced long-term blockade of spinal adrenergic analgesia: reversal by morphine and naloxone.

Alpha agonists [noradrenaline (NA) and ST-91] inhibit the release of substance P (SP) from the spinal cord and block the biting, licking, scratching syndrome produced by intrathecal SP suggesting that these agents produce analgesia by an interaction with SP systems. In this study we determined the effect of a desensitizing regimen of SP (15 micrograms X 2 at a 30-min interval) on analgesia produced by intrathecal NA in the rat tail-flick test. When NA was injected immediately after the regimen or after a 90-minute delay, NA analgesia was blocked. This blockade persisted up to 11 days after exposure to SP. Exposure to a single dose of SP (15 or 30 micrograms) also blocked NA acutely, but the long-term blockade did not last as long. An identical effect was observed with ST-91. SP (15 micrograms X 2) potentiated the analgesic action of morphine acutely, but no interaction was observed 4 to 7 days later. Pretreatment with morphine and naloxone prevented the long-term blockade by SP. The effect of naloxone was not reversed by naltrexone suggesting that occupation of opiate receptors rather than an apparent agonist effect of naloxone caused the protection. Pretreatment with clonidine had only a slight effect on long-term blockade, but yohimbine was without effect. The present study describes a new long-term interaction between SP and alpha-2 agonists in the spinal cord. The mechanism(s) of the observed blockade by SP remains to be elucidated. However, there appears to be a functionally significant interaction between opiate and alpha-2 receptors in the spinal cord.

Reduction of fresh gas flow requirements by a circle-modified bain breathing circuit.

We modified a Bain circuit by placing the circuit into the Y piece of a standard carbon dioxide absorber circle, connecting the fresh gas hose on the anesthetic machine to the Bain's fresh gas inlet, and occluding the circle's fresh gas inlet. This circle-modified Bain breathing circuit was studied to evaluate whether it reduces fresh gas flow requirements. The Bain and modified Bain steady states were analyzed by mechanical and computer modeling. The mechanical model consisted of an artificial lung ventilated to steady state. Carbon dioxide was measured with capnography. Computer modeling was by compartmental analysis calculated with spread-sheet software. Steady-state solutions were obtained by numeric analysis. The circle-modified Bain greatly reduced retention of carbon dioxide. For example, with 1-liter tidal volumes, 10-liter minute volumes (10 breaths per minute), and a 2.1 L/min fresh gas flow, the steady-state end-tidal carbon dioxide values of the Bain and modified Bain were 9.3 and 4.6%, respectively, in the physical model (carbon dioxide inflow of 230 ml/min). Results from the mechanical model helped validate the computer model.

Vascular effects of a modified cold pressor test in spinal cord injured and able-bodied men.

The vascular reflex responses of the hands of ten spinal cord injured (SCI) men (sensory and motor complete) to a modified cold pressor test were compared to ten age-matched, able-bodied men. The skin temperature of the left index finger was measured before, during, and after the immersion of the feet in ice water for 20 seconds. The heart rate and blood pressure were measured 5 minutes before and 15 minutes after the cold stimulus. The able-bodied subjects showed an immediate vasoconstriction and fall in finger temperature after cold stimulation of the feet, followed by vasodilation and an increase in finger temperature (p < .0001), whereas, the SCI subjects did not show any change in finger temperature during this test. Prior to application of the cold stimulus, the SCI subjects had a significantly low diastolic blood pressure compared with the diastolic blood pressure of able-bodied subjects, which "normalized" after the cold stimulus. These data support the concept that regulation of vascular tone occurs at both spinal and supraspinal levels.