Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI-LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT).

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disorder characterized by deficient activity of arylsulfatase B enzyme (ASB) resulting in cellular accumulation of dermatan sulfate (DS) and chondroitin sulfate (CS) that leads to cell injury. Urinary glycosaminoglycans (GAG) are often used as a biomarker in MPS diseases for diagnosis and to monitor treatment efficacy. This study evaluated leukocyte GAGs (leukoGAG) and skin GAGs as alternate biomarkers representing intracellular GAG changes in patients with MPS VI and treated with enzyme replacement therapy (ERT). In addition, we evaluated corneal opacification measurements (COM) and carotid intima media thickness (CIMT) as indicators of GAG accumulation and tissue injury. The study was performed in a serial two-step design in a single center. A quantitative method to measure leukoGAG levels in leukocytes was developed in Study 1 to compare the GAG levels between MPS VI patients and a control group and to assess correlations between leukoGAG and urineGAG. Study 2 validated the leukoGAG measurement, assessed the effect of ERT infusion on leukoGAG and ASB activity in leukocytes, identified correlations between leukoGAG and other biomarkers, and assessed differences in GAG accumulation between MPS VI patients and control subjects. In Study 1, leukoCS and leukoDS levels were significantly higher in the MPS VI group than the control group (leukoCS: 37.9 ± 10.2 and 2.9 ± 1.5 µg/µg protein, respectively, p = 0.005; leukoDS: 0.26 ± 0.2 and 0.0 ± 0.0 µg/µg protein, respectively, p = 0.028) with positive correlations between leukoCS and urine CS and leukoDS and urineDS. In Study 2, leukoCS (32.0 ± 11.8 vs 6.9 ± 3.1 µg/mg protein, p = 0.005) and leukoDS (0.4 ± 0.1 and 0.2 ± 0.1 µg/mg protein, p = 0.020) were significantly higher compared with control subjects. Thus, these results highlight the potential of leukoGAG as a new biomarker representing intracellular GAG accumulation in MPS VI patients and may be valuable for patient management.

Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil.

Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy (ERT) of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally available small molecule that results in the synthesis of odiparcil-linked GAGs facilitating their excretion and reducing cellular and tissue GAG accumulation. Improve MPS treatment was a Phase 2a study of the safety, pharmacokinetics/pharmacodynamics, and efficacy of two doses of odiparcil in patients with MPS VI. The core study was a 26-week, randomized, double-blind, placebo-controlled trial in patients receiving ERT and an open-label, noncomparative, single-dose cohort not receiving ERT. Patients aged ≥ 16 years receiving ERT were randomized to odiparcil 250 or 500 mg twice daily or placebo. Patients without ERT received odiparcil 500 mg twice daily. Of 20 patients enrolled, 13 (65.0%) completed the study. Odiparcil increased total urine GAGs (uGAGs), chondroitin sulfate, and dermatan sulfate concentrations. A linear increase in uGAG levels and odiparcil exposure occurred with increased odiparcil dose. Odiparcil demonstrated a good safety and tolerability profile. Individual analyses found more improvements in pain, corneal clouding, cardiac, vascular, and respiratory functions in the odiparcil groups vs placebo. This study confirmed the mechanism of action and established the safety of odiparcil with clinical beneficial effects after only a short treatment duration in an advanced stage of disease. Further assessment of odiparcil in younger patients is needed.

A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH.

BACKGROUND: Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. METHODS: In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis. RESULTS: A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo. CONCLUSIONS: In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.).

Menstrual Cycle, Vocal Performance, and Laryngeal Vascular Appearance: An Observational Study on 17 Subjects.

OBJECTIVE: To assess the anatomical and functional features of the vocal folds during different phases of the female menstrual cycle. METHODS: An observational study of 17 healthy fertile female volunteers not using hormonal contraception was carried out. Each volunteer underwent two examinations: first, during the early days of the menstrual cycle when progesterone levels are low (p-depletion), and second, during premenstruation when progesterone levels are high (p-peak). The workup included blood hormone levels, Voice Handicap Index, acoustic analysis, rigid telescopy, stroboscopy, and narrow band imaging. The videos were evaluated by blinded observers. RESULTS: The participants' mean age was 31.7 ± 5.6 (range 23-43). Progesterone levels were 13- to 45-fold higher in p-peak relative to p-depletion. No significant differences were detected in Voice Handicap Index scores, stroboscopic reports, or acoustic analysis between p-peak and p-depletion examinations. Analyzing the rigid telescopy and narrow band imaging videos, the observers tended to estimate the different laryngeal subsites more vascularized during the p-peak examination. Moreover, this tendency was significantly correlated with blood progesterone levels during the p-depletion examinations; the lower the blood progesterone levels were during p-depletion, the higher the probability for the observers to estimate the p-peak examinations more vascularized (P value = 0.024). CONCLUSIONS: Alterations in laryngeal vascular characteristics are evident throughout the menstrual cycle and may suggest increased congestion during premenstrual days. Variations in progesterone levels during the menstrual cycle correlate with laryngeal vascular changes. Hormone-related alterations in vocal folds' vascularity may have a role in the variability of vocal performance in certain women.

Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion.

Context: Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death. Objective: We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers. Design, Setting, and Participants: In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index-matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11ß-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed. Results: Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 pm to 10 pm [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 pm to 2 am (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 pm and 250 mg at 10 pm, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 pm to 10 pm (AUC difference: -0.06 nmol/L/h; P = 0.85); 10 pm to 2 am (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 pm to 2 pm (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment. Conclusions: In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6.

Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. METHODS: This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3-25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in all patients who received one or more doses of the study drug. The trial is registered with ClinicalTrials.gov, number NCT01302600. FINDINGS: The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and -1·82 for placebo (treatment difference 2·00 points, 96% CI -0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. INTERPRETATION: Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. FUNDING: AFM Téléthon and Trophos SA.

Evaluating Osseointegration Into a Deeply Porous Titanium Scaffold: A Biomechanical Comparison With PEEK and Allograft.

STUDY DESIGN: This was a biomechanical push-out testing study using a porcine model. OBJECTIVE: The purpose was to evaluate the strength of implant-bone interface of a porous titanium scaffold by comparing it to polyetheretherketone (PEEK) and allograft. SUMMARY OF BACKGROUND DATA: Osseointegration is important for achieving maximal stability of spinal fusion implants and it is desirable to achieve as quickly as possible. Common PEEK interbody fusion implants appear to have limited osseointegration potential because of the formation of fibrous tissue along the implant-bone interface. Porous, three-dimensional titanium materials may be an option to enhance osseointegration. METHODS: Using the skulls of two swine, in the region of the os frontale, 16 identical holes (4 mm diameter) were drilled to 10 mm depth in each skull. Porous titanium, PEEK, and allograft pins were press fit into the holes. After 5 weeks, animals were euthanized and the skull sections with the implants were cut into sections with each pin centered within a section. Push-out testing was performed using an MTS machine with a push rate of 6 mm/min. Load-deformation curves were used to compute the extrinsic material properties of the bone samples. Maximum force (N) and shear strength (MPa) were extracted from the output to record the bonding strength between the implant and surrounding bone. When calculating shear strength, maximum force was normalized by the actual implant surface area in contact with surrounding bone. RESULTS: Mean push-out shear strength was significantly greater in the porous titanium scaffold group than in the PEEK or allograft groups (10.2 vs. 1.5 vs. 3.1 MPa, respectively; P < 0.05). CONCLUSION: The push-out strength was significantly greater for the implants with porous titanium coating compared with the PEEK or allograft. These results suggest that the material has promise for facilitating osseointegration for implants, including interbody devices for spinal fusion. LEVEL OF EVIDENCE: N/A.

Effect of body weight and BMI on the efficacy of levonorgestrel emergency contraception.

OBJECTIVES: To further evaluate the effect of weight and body mass index (BMI) on the efficacy of levonorgestrel emergency contraception. METHODS: Data from two large, multicenter, randomized controlled trials designed to assess emergency contraceptive efficacy were pooled to evaluate the effect of weight and BMI on pregnancy rates among women who received levonorgestrel. Descriptive methods (comparison of means and distributions according to pregnancy status and pregnancy rates across weight and BMI categories) as well as cubic spline modeling were used to describe the relationship between pregnancy risk and weight/BMI. RESULTS: The analysis population comprised 1731 women, among whom 38 pregnancies were reported. Women for whom levonorgestrel was not effective in preventing pregnancy had a significantly higher mean body weight and BMI than women who did not become pregnant (76.7 vs. 66.4 kg, p<.0001; 28.1 vs. 24.6 kg/m², p<.0001). The estimated pregnancy rate increased significantly from 1.4% [95% confidence interval (CI): 0.5%-3.0%] among the group of women weighing 65-75 kg to 6.4% (95% CI: 3.1%-11.5%) and 5.7% (95% CI: 2.9%-10.0%) in the 75-85 kg and >85 kg groups, respectively. Statistical modeling demonstrated a steep increase in pregnancy risk starting from a weight near 70-75 kg to reach a risk of pregnancy of 6% or greater around 80 kg. Similar results were obtained for statistical modeling of BMI as well as when the two studies were analyzed individually. CONCLUSIONS: All analyses showed a significant drop in the efficacy of levonorgestrel emergency contraception with increasing body weight, with pregnancy risk in the higher weight categories similar to expected rates in the absence of contraception. Like body weight, increasing BMI was highly correlated with increased pregnancy risk.

Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial.

BACKGROUND: Although reperfusion injury has been shown to be responsible for cardiomyocytes death after an acute myocardial infarction, there is currently no drug on the market that reduces this type of injury. TRO40303 is a new cardioprotective compound that was shown to inhibit the opening of the mitochondrial permeability transition pore and reduce infarct size after ischemia-reperfusion in a rat model of cardiac ischemia-reperfusion injury. METHODS: In the rat model, the therapeutic window and the dose effect relationship were investigated in order to select the proper dose and design for clinical investigations. To evaluate post-ischemic functional recovery, TRO40303 was tested in a model of isolated rat heart. Additionally, TRO40303 was investigated in a Phase I randomized, double-blind, placebo controlled study to assess the safety, tolerability and pharmacokinetics of single intravenous ascending doses of the compound (0.5 to 13 mg/kg) in 72 healthy male, post-menopausal and hysterectomized female subjects at flow rates from 0.04 to 35 mL/min (EudraCT number: 2010-021453-39). This work was supported in part by the French Agence Nationale de la Recherche. RESULTS: In the vivo model, TRO40303 reduced infarct size by 40% at 1 mg/kg and by 50% at 3 and 10 mg/kg given by intravenous bolus and was only active when administered before reperfusion. Additionally, TRO40303 provided functional recovery and reduced oxidative stress in the isolated rat heart model.These results, together with pharmacokinetic based allometry to human and non-clinical toxicology data, were used to design the Phase I trial. All the tested doses and flow rates were well tolerated clinically. There were no serious adverse events reported. No relevant changes in vital signs, electrocardiogram parameters, laboratory tests or physical examinations were observed at any time in any dose group. Pharmacokinetics was linear up to 6 mg/kg and slightly ~1.5-fold, hyper-proportional from 6 to 13 mg/kg. CONCLUSIONS: These data demonstrated that TRO40303 can be safely administered by the intravenous route in humans at doses expected to be pharmacologically active. These results allowed evaluating the expected active dose in human at 6 mg/kg, used in a Phase II proof-of-concept study currently ongoing.

Ulipristal acetate for emergency contraception: postmarketing experience after use by more than 1 million women.

OBJECTIVE: To describe the safety of ulipristal acetate in emergency contraception. STUDY DESIGN: Postmarketing pharmacovigilance data collection. RESULTS: A total of 553 women experienced 1049 adverse drug reactions. The most frequent (n,%) were pregnancies (282, 6.8%); nausea, abdominal pain and vomiting (139, 13.3%); headache, dizziness (67, 6.4%); and metrorrhagia, menses delay and breast symptoms (84, 8.0%). Including data from clinical trials, 376 pregnancies have been reported in total, 232 (62%) with a known outcome: 28 live births (29 newborns), 34 miscarriages, 151 induced abortions, 4 ectopics and 15 which are ongoing. CONCLUSIONS: No safety concern emerges from a sizable database of reported adverse reactions following ulipristal acetate exposure among varying ethnicities and regions. Postapproval data confirm the safety profile described during the clinical trials. IMPLICATIONS: Use of ulipristal acetate for emergency contraception in a variety of settings and among diverse populations indicate that it is safe and without unexpected or serious adverse events.

Drug discovery and development for spinal muscular atrophy: lessons from screening approaches and future challenges for clinical development.

Spinal muscular atrophy (SMA) is a progressive pediatric neuromuscular disease. Because disease severity is related to survival motor neuron (SMN) protein levels, increasing SMN production from the SMN2 gene has been a major SMA drug-discovery strategy. Cell-based assays using neuronal cell lines and cells from SMA patients have identified compounds that can increase SMN protein expression. Our experience of using such an assay signaled potential risks to be avoided through the use of appropriate secondary assays. In addition to the 'SMN2' approach, compensating for decreased SMN protein or neuroprotection are also potential SMA drug-discovery strategies. SMA clinical trials are now a reality; however, trial design in a slowly progressing rare disease such as SMA will present an interesting future challenge.

Olesoxime (TRO19622): A Novel Mitochondrial-Targeted Neuroprotective Compound.

Olesoxime (TRO19622) is a novel mitochondrial-targeted neuroprotective compound undergoing a pivotal clinical efficacy study in Amyotrophic Lateral Sclerosis (ALS) and also in development for Spinal Muscular Atrophy (SMA). It belongs to a new family of cholesterol-oximes identified for its survival-promoting activity on purified motor neurons deprived of neurotrophic factors. Olesoxime targets proteins of the outer mitochondrial membrane, concentrates at the mitochondria and prevents permeability transition pore opening mediated by, among other things, oxidative stress. Olesoxime has been shown to exert a potent neuroprotective effect in various in vitro and in vivo models. In particular olesoxime provided significant protection in experimental animal models of motor neuron disorders and more particularly ALS. Olesoxime is orally active, crosses the blood brain barrier, and is well tolerated. Collectively, its pharmacological properties designate olesoxime as a promising drug candidate for motor neuron diseases.

Defining survival as an outcome measure in amyotrophic lateral sclerosis.

OBJECTIVES: To examine how respiratory interventions affect survival as an outcome measure and to define survival rate for trials in amyotrophic lateral sclerosis. DESIGN AND SETTING: We reviewed the data of 3 phase 3 clinical trials and examined differences in times to death, tracheostomy, and permanent assisted ventilation. We assessed the outcomes with chi(2) and Fisher exact tests for categorical variables and unpaired, 2-tailed t tests for continuous variables. We used Kaplan-Meier methods to estimate the differences in survival times between interventions. A power analysis generated sample size estimates for different end points. PATIENTS: In all, 2077 patients in 2 phase 3 trials of xaliproden and 400 patients in a phase 3 trial of pentoxifylline. MAIN OUTCOME MEASURES: Death or combined death, tracheostomy, or permanent assisted ventilation. RESULTS: Of 745 deaths, 611 (82.0%) were owing to respiratory failure and 134 (18.0%) to other causes. The use of respiratory interventions across centers ranged from 0% to 6.6% (P = .001) of patients for tracheostomy and 11.1% to 23.1% (P = .05) of patients for noninvasive ventilation. Twelve of 55 patients (21.8%) undergoing tracheostomy had a vital capacity of 50% or more. Mean (SD) survival time was 457.9 (3.1) days using a combined end point and 467.2 (2.9) days with death alone as the outcome (P = .02). An estimated sample size to detect a 10% difference at 18 months between groups was 490 patients per arm for the combined end point and 410 patients for death alone. CONCLUSIONS: Tracheostomy and permanent assisted ventilation are not equivalent to death in amyotrophic lateral sclerosis. The use of respiratory interventions differs between centers, leading to variability in combined outcome assessments. The time to the end point can differ significantly depending on its definition, and combining outcomes does not reduce the estimated sample size of a trial. The death rate alone is the least variable and most easily identifiable measure of survival rate in amyotrophic lateral sclerosis.

Vocal fold augmentation with calcium hydroxylapatite: twelve-month report.

OBJECTIVES: To evaluate the long-term effectiveness of calcium hydroxylapatite (CaHA) vocal fold injection for patients with glottal insufficiency. STUDY DESIGN: Multicenter, open-label, prospective clinical study of CaHA vocal fold injection. METHODS: Each patient served as his/her own control. Voice-related outcome measures were collected for pre-injection, 1, 3, 6, and 12 months. RESULTS: Sixty-three patients were available for evaluation. Fifty-three percent of the injection procedures were done in the office. Fifty-seven percent of patients were diagnosed with unilateral paralysis and 43% with glottal incompetence with mobile vocal folds. Patient satisfaction 12 months after injection showed 67% reporting a significant improvement in voice and 81% reporting at least a moderate improvement in voice. Utilizing the Voice Handicap Index-10, visual analog scale (vocal effort), Consensus Assessment Perceptual Evaluation V (judgments of voice severity), and objective voice measures of glottal closure (maximum phonation time and S:Z ratio), paired t tests showed significant improvements after treatment. A 22% further treatment rate was found at the 12-month time point. CONCLUSIONS: One-year results in this large cohort of patients with glottal incompetence treated with CaHA vocal fold injection demonstrate that excellent clinical results were achieved.

Specific antinociceptive activity of cholest-4-en-3-one, oxime (TRO19622) in experimental models of painful diabetic and chemotherapy-induced neuropathy.

Diabetes and cancer chemotherapies are often associated with painful neuropathy. The mechanisms underlying neuropathic pain remain poorly understood, and the current therapies have limited efficacy and are associated with dose-limiting side effects. We recently described the pharmacological characterization of cholest-4-en-3-one, oxime (TRO19622), a cholesterol-like compound, that significantly reduced axonal degeneration and accelerated recovery of motor nerve conduction in a model of peripheral neuropathy induced by crushing the sciatic nerve. These results triggered investigation of efficacy in other preclinical models of peripheral neuropathy. Here, we report evidence that daily oral administration of TRO19622, while similarly improving motor nerve conduction impaired in streptozotocin-induced diabetic rats, also reversed neuropathic pain behavior as early as the first administration. Further exploration of these acute antinociceptive effects demonstrated that TRO19622 was also able to reverse tactile allodynia in vincristine-treated rats, a model of chemotherapy-induced neuropathic pain. It is interesting to note that TRO19622 did not have analgesic activity in animal models of pain produced by formalin injection, noxious thermal or mechanical stimulation, or chronic constriction injury of the sciatic nerve, indicating that painful diabetic or chemotherapy-induced neuropathies share a common mechanism that is distinct from acute, inflammationdriven, or lesion-induced neuropathic pain. These results support the potential use of TRO19622 to treat painful diabetic and chemotherapy-induced neuropathies.

Kinematic analysis of the relationship between the grade of disc degeneration and motion unit of the cervical spine.

STUDY DESIGN: Kinetic MRIs of cervical spines were obtained and analyzed according to the amount of motion and the degenerative grade of the intervertebral disc. OBJECTIVE: To define the relationship between the grade of disc degeneration and the motion unit of the cervical spine and elucidate changes in the role of each cervical spine unit during flexion-extension motion caused by degeneration. SUMMARY OF BACKGROUND DATA: Degenerative changes in the cervical disc occur with age. The correlation between the degree of cervical disc degeneration and extent of cervical spine mobility has not yet been determined. The effect of degeneration on the overall motion of the functional spinal unit also remains undefined. METHODS: We studied 164 patients with symptomatic neck pain. The cervical intervertebral discs were graded by spine surgeons according to the degenerative grading system (Grades I to V). All radiologic data from kinetic MRIs were recorded on a computer for subsequent measurements. All measurements and calculations for translational motion and angular variation of each segment were automatically performed by a computer analyzer. RESULTS: The translational motion in discs with Grade II degeneration (mild degeneration) increased to Grade III degeneration (higher degeneration). However, the translational motion and angular variation significantly decreased for the Grade V (severe degeneration). For patients with relatively low grades of degeneration, Grades I and II discs, the C4-C5 and C5-C6 segmental units contributed the majority of total angular mobility of the spine. However, for the severely degenerated segments, Grade V discs, the contributions of the C4-C5 and C5-C6 U significantly decreased. CONCLUSION: The changes that occur with disc degeneration progress from the normal state to an unstable phase with higher mobility and subsequently to an ankylosed stage. This study evaluated the contribution of different levels to the changes in overall motion that occur with degeneration.

The voice and laryngeal dysfunction in stroke: a report from the Neurolaryngology Subcommittee of the American Academy of Otolaryngology-Head and Neck Surgery.

OBJECTIVE: Stroke is the third leading cause of death in the United States, behind heart disease and cancer. It affects as many as 5% of the population over 65 years old, and this number is growing annually due to the aging population. A significant portion of stroke patients that initially survive are faced with the risk of aspiration, as well as quality-of-life issues relating to impaired communication. The goal of this paper is to define the scope of practice in otolaryngology for these patients, and to review pertinent background literature. STUDY DESIGN: Consensus report and retrospective literature review. RESULTS: Otolaryngology involvement in these patients is critical to their rehabilitation, which often requires an interdisciplinary team of specialists. This committee presentation explores epidemiological data regarding the impact of stroke and its complications on hospitalizations. A pertinent review of neuroanatomy as it relates to laryngeal function is also discussed. State-of-the-art diagnostic and therapeutic procedures are presented. CONCLUSION: There is a well-defined set of diagnostic and therapeutic options for laryngeal dysfunction in the stroke patient. SIGNIFICANCE: Otolaryngologists play a critical role in the interdisciplinary rehabilitation team.

Vocal fold augmentation with calcium hydroxylapatite (CaHA).

OBJECTIVES: Evaluate the effectiveness of CaHA injection for patients with glottal incompetence. METHODS: Multi-center, open-label, prospective clinical study with each patient serving as his/her own control. Voice-related outcome measures were collected for pre-injection and 1, 3, and 6 months. RESULTS: Sixty-eight patients were available for evaluation. Fifty percent of the injection procedures were done in office. Fifty-seven percent were diagnosed with unilateral paralysis and 42% with glottal incompetence with mobile vocal folds. Patient satisfaction 6 months post showed 56% had significantly improved voice and 38% reported moderately improved voice. Paired t tests from baseline to 6 months showed significant improvements on the VHI and VAS (vocal effort), CAPE-V judgments of voice severity and videoendostroboscopy ratings of glottal closure, and objective voice measures of glottal closure (MPT and S:Z ratio). CONCLUSIONS: Preliminary results in this large cohort of patients demonstrate excellent clinical results.

Bipolar radiofrequency-induced thermotherapy (rfitt) for the treatment of spasmodic dysphonia. A report of three cases.

The symptoms of adductor spasmodic dysphonia are most commonly palliated by periodic botulinum toxin injections. The need for repeated injections, difficulty in obtaining injections and cost make this form of treatment intolerable for some patients. To address these concerns, we propose a new treatment approach utilizing trans-oral recurrent nerve coagulation. The goal is to weaken the force of laryngeal closure during spasms by creating fibrosis of the terminal branches of one recurrent nerve through coagulation. Under general anesthesia without paralysis, an electrical stimulator is used to identify the region within the thyroarytenoid muscle that produces the greatest contraction with minimal stimulation. The radiofrequency laryngeal probe or electrocautery device is introduced into this position, and energy is delivered. The location of the region of maximal stimulation is usually just lateral and anterior to the vocal process of the arytenoids. Between 1989 and 2000, seven patients were treated with electrocautery. To achieve remission of spasms, three patients needed three sessions, four needed two sessions and one only one session. Since 2001, three patients have achieved remission of spasms with a single treatment with radiofrequency during which 80 J was delivered. Voice results are comparable to those obtained with botulinum toxin. Initially, the voice is breathy and laryngeal examination shows complete vocal fold immobility. After 1-2 months, the voice improves and examination reveals unilateral hypomobility. Trans-oral recurrent nerve coagulation is an effective alternative to botulinum toxin injections.