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Background Clinical photonumeric scales have been developed and validated to objectively measure the effectiveness of aesthetic treatments in specific anatomical areas; however, these are based on the typical features of Caucasian patients. No clinical scale for Asian calf appearance currently exists. Objective To develop and validate a calf assessment scale for use in the female Asian patient population. Methods and materials During 2 validation sessions, 13 raters assessed calf images of female Asian subjects (N = 35) viewed from behind with feet flat on the floor (at rest) and on tiptoes (dynamic). Images were rated from 0 (very slim, linear profile) to 4 (very severe convex profile). Results Inter-rater and intra-rater reliability were "substantial" (≥0.6, intraclass correlation coefficient [ICC] and weighted kappa) for the calf-at rest, calf-dynamic, and calf summary score. Reliability was "substantial" for calf-at rest and calf-dynamic (≥0.6, ICC and weighted kappa) and "almost perfect" (0.85) for the calf summary score. BMI and calf circumference were highly correlated with scale ratings, and calf circumference was a significant predictor. Conclusion This new photonumeric assessment scale has value for assessing the female Asian calf, providing a standardized measure of calf appearance in clinical practice and clinical research settings.

Cholangiocarcinoma (CCA) is a cancer arising from the epithelium of intrahepatic or extrahepatic bile ducts. Cholangiocarcinoma often has a poor prognosis due to late diagnosis and the incidence and mortality rate of intrahepatic CCA appear to be increasing. Current therapies include surgical resection, orthotopic liver transplantation, chemotherapy/chemoradiation and palliative care. Depending on the location, the 5-year survival for CCA ranges from 27–60%. Emerging new therapies are currently being developed for treating CCA include immunotherapy, altering the tumor microenvironment, targeting growth factor gene mutations and signal pathways and that control tumor growth, and targeting gene therapy. The objective of this paper is to summarize the research that is currently ongoing for treating this challenging disease.

As the number of aesthetic treatments has grown, so have the number of photonumeric assessment scales used to compare the effectiveness of these aesthetic treatments in specific anatomical areas; however, these are primarily based on Caucasian features.To assess the validity of the first aesthetic scale for assessing the slope of the Asian forehead. A secondary objective was to correlate this scale with subject demographics and baseline characteristics.During 2 validation sessions, 13 raters assessed full frontal and lateral facial images of female (n = 28; 56.0%) and male (n = 22; 44%) subjects. For each subject, the severity of forehead sloping was graded from 0 (convex forehead, optimal forehead volume) to 4 (concave forehead, very severe sloping). Raters also assessed the age of each subject and the estimated aesthetic treatment effort required to treat each subject.Inter-rater reliability was "substantial" with scores of 0.67 and 0.68 for the first and second validation sessions, indicating high reliability. BMI showed the highest correlation with the scale and was a significant predictor in the final regression model.This photonumeric assessment scale will be useful for assessing the slope of the Asian forehead in both clinical and research settings.

As the number of different aesthetic treatments increase, numerous photonumeric assessment scales have been developed and validated to measure the effectiveness of these new treatments and techniques. Photonumeric rating scales have been developed to objectively assess improvements in anatomical areas; however, these have been based on the features of Caucasian patients.To develop and validate a Chin Projection Scale for use in the female Asian patient population.During 2 validation sessions, 13 raters assessed full frontal and lateral facial views of 50 Asian subjects and also estimated their age and the aesthetic treatment effort required for each subject. Chin projection was rated on a scale from 0 (optimal) to 4 (very severely receding).Inter-rater reliability was 0.80 (substantial) for Validation Session 1 and 0.83 (almost perfect) for Validation Session 2. The results for Estimated Age and Estimated Treatment Effort were essentially the same.This study demonstrated the validity of the first photonumeric assessment scale for assessing the appearance of the female Asian chin. This new scale will provide a standardized measure of chin projection for Asian patients in clinical practice and clinical research settings.

A microfocused ultrasound system with visualization (MFU-V) is currently indicated for use as a noninvasive dermatological aesthetic treatment to lift the eyebrows, lax submental and neck tissue, and improve lines and wrinkles of the décolleté.To determine the existence of any safety signals when combining MFU-V with botulinum toxin-A and/or semipermanent and temporary dermal fillers.A retrospective chart review was performed using subjects who received aesthetic treatments including incobotulinumtoxinA injection, cohesive polydensified matrix hyaluronic acid (CPM HA) dermal fillers, and calcium hydroxylapatite (CaHA) dermal fillers within 6 months of treatment with MFU-V in the same or different anatomic areas.All subjects (N = 101; 96 female; 25-70 year old) received MFU-V, 18% received incobotulinumtoxinA injections, and 81% were treated with CPM HA and/or CaHA fillers. Seven adverse events (7%) were reported: bruising/purpura (n = 4), swelling (n = 1), paresthesia (n = 1), and herpes simplex virus (HSV) outbreak (n = 1). Only the HSV outbreak was considered to be related to combined treatments.Although limited by relatively few subjects, the results of the present study suggest that the safety profile of MFU-V combined with other aesthetic products is consistent with the safety profiles of the individual treatments.

Hyaluronic acid (HA) dermal fillers are commonly used in cosmetic dermatology. Due to differences in their physical characteristics, HA fillers demonstrate different sensitivity to degradation by hyaluronidase (Hase) because of HA concentration and differences in cross-linking. Similarly, there are differences in the activity of Hase products depending on source and concentration.The primary objective was to demonstrate the differences in potency and activity of 5 Hase products when used to degrade 5 different HA products using a human in vivo model.The study subject was a healthy, consenting adult woman scheduled to undergo abdominoplasty. Skin to be excised was injected with 0.1 to 0.2 mL of each filler (10 injections each) leaving a visible lump. Immediately afterward, the HA lumps were injected with 4 IU of each Hase product every 2 minutes until the HA lumps were no longer visible or palpable. This procedure was repeated after 30 days. Injected tissues were excised after abdominoplasty for histological analysis.The 5 Hase products displayed a wide range of doses and times required to completely degrade the 5 HA products ranging from2 to16 minutes.Cosmetic practitioners should familiarize themselves with differences in HA and Hase products.

With the increased popularity of minimally invasive cosmetic treatments, this study evaluates the efficacy and safety of microfocused ultrasound with visualization (MFU-V) for tightening lax skin above the elbow.Subjects were treated bilaterally above the elbows with MFU-V using transducers with different focal depths. Photographs were taken before treatment and at 90- and 180-day follow-ups. Masked observer ratings and physician and subject global aesthetic improvement scales (PGAIS and SGAIS) were completed at follow-ups. Safety, based on adverse event (AE) incidence, was assessed.Masked blinded assessment was completed at 90 days; 56% showed aesthetic improvement. Overall improvement in SGAIS was 83% and 81% at 90 and 180 days, respectively. The overall improvement in PGAIS was 94% at both 90 and 180 days. Patient satisfaction questionnaires showed that 83% noticed improvements in elbow characteristics at 90 days, with 81% still indicating improvement at 180 days. No serious AEs or treatment-related AEs were reported.This pilot study suggests that MFU-V is a safe and promising nonsurgical option for the treatment of skin laxity above the elbow. Based on the positive results of this study, a larger trial is warranted together with testing different treatment densities to optimize this noninvasive approach.

Background A previous pilot study demonstrated microfocused ultrasound with visualization (MFU-V) to lift and tighten the decollete produced significant and durable aesthetic improvements. Objective To further evaluate the safety and effectiveness of MFU-V for improving lines and wrinkles of the decollete in a larger patient population. Materials and methods Healthy women with moderate-to-severe decollete skin lines and wrinkles were enrolled. After obtaining digital images, MFU-V was administered using 3 transducers emitting ultrasound at frequencies of 4 MHz and a focal depth of 4.5 mm, 7 MHz/3.0 mm, and 10 MHz/1.5 mm. During the procedure, 280 lines of discrete thermal coagulative points 25 mm long and 2 to 3 mm apart were applied to the treatment area. Additional imaging for masked assessments and live assessments were completed at 90 and 180 days. Results Among the evaluable subjects, 77 (66.4%) demonstrated aesthetic improvement at 180 days based on blinded assessments. Approximately, 75% and 65% of treated subjects demonstrated some degree of improvement at 90 and 180 days, respectively, and most were satisfied with treatment outcomes. Adverse events were generally mild. Conclusion A single MFU-V treatment provided significant aesthetic improvement for moderate-to-severe decollete lines and wrinkles for at least the 180-day duration of the study.

RT002 is a new injectable BoNTA product. This formulation limits the spread of BoNTA, potentially permitting safe administration of larger doses and possibly extending its duration of action.This phase 1/2 clinical study was designed to establish the safety of RT002 for the treatment of moderate-to-severe glabellar lines.Subjects were randomized into four groups (N=12/group). Cohorts 1-3 received escalating doses of RT002 ranging from half the equivalent dose of approved toxins up to twice the current dose levels. The safety of each dose was confirmed prior to administering the next dose. Subjects in Cohort 4 were treated with the highest dose and observed for 36 weeks or until GLSS returned to baseline.All doses of RT002 were well-tolerated. Common AEs were headache and mild injection site reactions. At Week 4, all doses of RT002 were highly effective at maximum frown. Cohort 4 achieved 7 month median duration. At 6 months, 80% of subjects maintained a ≥1-point improvement in Investigator GLSS and 60% maintained WSS of None or Mild. Study limitations include an open-label design and modest number of subjects.RT002 is a safe and effective BoNTA product with an extended duration of action.

SummaryBackground Hair loss is a common condition among women with a range of causes including nutritional deficiencies. Aims To review the clinical data supporting the use of an oral marine supplement designed to promote hair growth. Patients/Methods Adult women with temporary thinning hair. Following an initial pilot study, five randomized, double-blind studies assessed the effectiveness of the oral marine supplement for promoting hair growth. Each study was approved by one or more institutional review boards. Results Together, these studies demonstrated the ability of oral marine supplements to increase the growth of terminal and vellus hairs, increase the diameter of terminal and vellus hairs, and decrease hair loss. This product is beneficial for men as well as women. Conclusions A dietary supplement containing a marine complex and other natural ingredients can safely and effectively promote hair growth and decrease hair shedding in women and men with thinning hair.

Objective: The efficacy of low-level laser therapy for noninvasive body contouring has been previously demonstrated in clinical trials leading to its market clearance. Subjects achieved these beneficial effects following three weekly low-level laser therapy treatments for two weeks. The objective of this study was to determine if the same aesthetic benefit can be achieved following one weekly low-level laser therapy treatment for six weeks. Setting: Two private dermatology practices. Participants: Healthy adults with a body mass index of 25 to 40kg/m2 (N=54). Measurements: Subjects underwent one weekly low-level laser therapy procedure for six consecutive weeks using a device consisting of six 17mW, 635nm red diodes. Waist, hip, thigh, and upper abdomen circumference were measured weekly. Study success criteria was a 4.5-inch mean decrease in combined body circumference. Results: The mean decrease in combined circumference reduction at six weeks was 5.4 inches (p

Medical information departments are responsible for providing information regarding the drugs the company manufactures and the diseases these drugs treat. The medical information departments of orphan drug manufacturers face unique challenges. Although they receive fewer inquiries, those received usually require sophisticated and time-consuming responses, often based on unpublished information and with greater reliance on rare disease experts. Worldwide distribution results in interactions with non-English-speaking individuals and requires familiarity with international legal requirements. Orphan drug medical information staff has greater visibility and is more likely to be contacted regarding adverse events and assistance for investigator-initiated clinical studies. As primary sources of information for patients, they need to be familiar with patient advocacy groups, clinical trial enrollment, and sources of unapproved medications such as expanded access programs. The ideal orphan drug medical informatio...

Objective We hypothesized that subjects with obsessive-compulsive disorder (OCD) who received extended-release fluvoxamine (fluvoxamine ER) in a 12-week placebo-controlled trial would exhibit improvements in psychosocial domains of health-related quality of life (HRQOL) and that additional improvements would occur after a 40-week open-label extension trial. We also hypothesized that greater OCD symptom improvement in the first 12 weeks of treatment would be associated with greater HRQOL improvement after 52 weeks of treatment. Methods In the 12-week placebo-controlled trial, subjects were randomized to receive placebo or 100 mg/d of fluvoxamine ER and then titrated in weekly 50 mg increments to a final dose of 100 to 300 mg/d. All subjects enrolled in the 40-week extension trial followed a similar titration, during which they were maintained on their highest well-tolerated dose. Results After 12 weeks of treatment, fluvoxamine ER subjects experienced significantly greater decreases than placebo subjects in Yale-Brown Obsessive-Compulsive Scale scores ( P = .001). Both the active drug and placebo groups exhibited significant improvements in psychosocial domains of HRQOL; further improvement occurred after 40 weeks of open-label treatment with active drug. The greater the improvement in OCD severity at 12 weeks, the greater the improvement at 52 weeks in the psychosocial domains (Social Functioning r = −0.39, P = .027; Emotional Problems r = −0.37, P = .037; Mental Health r = −0.49, P = .004). Conclusion Improvement in Yale-Brown Obsessive-Compulsive Scale severity scores during treatment with fluvoxamine ER was associated with improvements in psychosocial aspects of HRQOL that increased over an extended period of treatment.

Sapropterin is approved to reduce blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin-responsive phenylketonuria. The current Food and Drug Administration—approved labeling states that sapropterin tablets should be dissolved in 4 to 8 oz of water or apple juice; however, numerous requests for information regarding the feasibility of administering crushed sapropterin tablets in infant formula or soft foods such as applesauce and pudding suggest that the current recommendations for administration may not be suitable for many infants and small children. To determine the safety of administering the medication in formula or soft foods, powdered tablets representing 200 mg of sapropterin were thoroughly mixed with applesauce, lemon pudding, and 3 brands of phenylalanine-free infant formula, incubated for up to 60 minutes at room temperature and then analyzed for sapropterin content. The results indicate there was no significant change in the amount of sapropterin present in any mixture after 60 minutes.

Alopecia and thinning hair are highly prevalent conditions affecting a large proportion of men and women. Diffused hair loss is often more difficult to diagnose in women, mostly due to over-reliance on the assumption of hormonal influences, and it is commonly treated with a multi-therapy approach. Clinical studies have demonstrated the effectiveness of a nutraceutical supplement to provide essential nutrients that aid in stimulating existing hair growth and reducing hair shedding. The supplement Viviscal® contains a proprietary blend of proteins, lipids, and glycosaminoglycans derived from sustainable marine sources. We present here a summary of studies that have examined the safety and efficacy of this nutraceutical; as well as discussions on hair loss and current therapies from a recently convened expert panel in dermatology and plastic surgery.

Cellulite refers to the dimpled appearance of skin occurring where the dermis is tethered by subcutaneous fibrous septa arranged perpendicularly to the skin surface.To demonstrate the safety and efficacy of a new system for vacuum-assisted precise tissue release for the treatment of cellulite.Adult women with moderate to severe cellulite (N = 55) underwent a single treatment. Post-treatment assessments were performed after 3 and 14 days; 1, 3, and 6 months; and at 1 year. Outcome measures included blinded assessments of subject photographs, a validated Cellulite Severity Scale (CSS), and the Global Aesthetic Improvement Scale. Subject satisfaction and pain ratings were also recorded.The mean baseline CSS score of 3.4 decreased to 1.3 at 3 months (p.0001) and 1.4 at 1 year (p.0001), with 47 subjects (93%) having ≥1-point improvements. Subject satisfaction was 85% at 3 months and 94% at 1 year. Transient treatment-related adverse events were mild in severity.This study demonstrates the safety, efficacy, and subject satisfaction with vacuum-assisted precise tissue release in the treatment of cellulite. There was no reduction in treatment benefits for up to 1 year. These results supported the Food and Drug Administration clearance of the device for the long-term reduction in the appearance of cellulite.

The discovery of gamma-hydroxybutyrate (GHB) over 40 years ago led to its immediate use as a general anesthetic agent. Subsequent research demonstrated that GHB is an endogenous compound in the mammalian brain and current research suggests that GHB is a probable neurotransmitter. In the United States, reports of anabolic effects lead to its misuse among body builders during the 1980's while the intoxicating properties of the drug lead to its popularization as a substance of abuse during the 1990's. GHB became associated with reports of drug-facilitated sexual assault and cases of physical dependence and withdrawal. Efforts to ban GHB caused increased use of GHB analogues and pro-drugs. Against this backdrop, GHB was being developed for the treatment of narcolepsy, leading to the approval of Xyrem (sodium oxybate) oral solution in 2002 for the treatment of cataplexy in patients with narcolepsy. A risk management program permits the safe handling and distribution of the approved product, minimizes the risk for diversion, provides professional and patient education about the risks and benefits of sodium oxybate, and includes physician and patient registries. Post-marketing surveillance indicates sodium oxybate has an acceptable safety profile and presents minimal risk for the development of physical dependence.

Sodium oxybate, also known as gamma-hydroxybutyric acid (GHB), was discovered in 1960 and has been described both as a therapeutic agent with high medical value and, more recently, a substance of abuse. The naturally occurring form of this drug is found in various body tissues but has been studied most extensively in the CNS where its possible function as a neurotransmitter continues to be studied. Sodium oxybate has been approved in different countries for such varied uses as general anaesthesia, the treatment of alcohol withdrawal and addiction, and, most recently, cataplexy associated with narcolepsy. During the 1980s, easy access to GHB-containing products led to various unapproved uses, including weight loss, bodybuilding and the treatment of sleeplessness, sometimes with serious long-term effects. The availability of these unapproved and unregulated forms of the drug led to GHB and its analogues being popularised as substances of abuse and subsequent notoriety as agents used in drug-facilitated sexual assault, or 'date rape', eventually leading to the prohibition of GHB sales in the US. Legal efforts to control the sale and distribution of GHB and its analogues nearly prevented the clinical development of sodium oxybate for narcolepsy in the US. However, following extensive discussions with a variety of interested parties, a satisfactory solution was devised, including legislative action and the development of the Xyrem Risk Management Program. Amendments to the US Controlled Substances Act made GHB a schedule I drug, but also contained provisions that allow US FDA-approved products to be placed under schedule III. This unique, bifurcated schedule for sodium oxybate/GHB allowed the clinical development of sodium oxybate to proceed and, in July 2002, it was approved by the FDA as an orphan drug for the treatment of cataplexy in patients with narcolepsy as Xyrem(sodium oxybate) oral solution. To promote the safe use of sodium oxybate, as well as alleviate concerns over possible diversion and abuse following product approval, a proprietary restricted drug distribution system was created, called the Xyrem Success Program. Components of the programme include a centralised distribution and dispensing system, a physician and patient registry, compulsory educational materials for patients and physicians, a specially trained pharmacy staff, a method for tracking prescription shipments, and an initial post-marketing surveillance programme. The system has created a unique opportunity to provide both physician and patient education and ongoing patient counselling, promoting greater drug safety and enhanced patient compliance.

Narcolepsy, a rare disease with a prevalence of 0.05% in the general population, affects an estimated 140,000 patients in the United States. Patients have been able to lead fuller personal and professional lives since the Food and Drug Administration approved sodium oxybate (Xyrem) in 2002 for treatment of cataplexy in patients with narcolepsy. Previously, gamma-hydroxybutyrate (GHB), the active ingredient of sodium oxybate, had been a substance of abuse, most notoriously as a date-rape drug. Public Law 106-172, the date-rape prohibition act enacted in 2000, was modified to allow the drug to be legally administered for medical purposes. Because of the apprehension regarding the risk of possible drug diversion after the approval of sodium oxybate and concerns about safety, the Xyrem Risk Management Program was created. This program has been successful in satisfying the needs of patients and physicians while ensuring responsible distribution of the drug.

Background Microfocused ultrasound has been shown to lift and tighten lax eyebrows, submental, and neck skin. Objective The aim of this study was to evaluate the safety and effectiveness of microfocused ultrasound to lift, tighten, and smooth the buttocks. Materials and methods Thirty-one subjects, with buttock skin laxity, were entered into the study. The right buttock was treated with microfocused ultrasound. Subjects were evaluated for up to 180 days for improvement in overall lifting and tightening of the buttock. Results Among subjects evaluated at 180 days, 89.5% showed improvement. However, when asked, most subjects would not recommend treatment to family or friends. Conclusion Although microfocused ultrasound clearly can be used to safely lift, tighten, and smooth the buttocks, better subject selection and newer developed transducers may lead to greater overall acceptance of this technique.

Behaviors induced in mice by intrathecal injections of either N-methyl-D-aspartate (NMDA) or kainic acid are modulated by NH2-terminal fragments of substance P, such as substance P-(1-7). The action of substance P-(1-7) on kainic acid depends on sigma receptor activity. The present study was designed to test the hypothesis that sigma receptor activity is also necessary for modulation of NMDA by substance P-(1-7). Intrathecal injection of mice with NMDA results in a brief burst of biting and scratching behaviors which decrease in intensity when NMDA is injected repeatedly at 2 min intervals. Pretreatment with 1,3-di-O-tolylguanidine (DTG), a ligand at both sigma 1 and sigma 2 sites, converted NMDA-induced desensitization to sensitization, thereby enhancing tonic NMDA receptor activity. Although haloperidol (30 min) alone was without effect, the potentiation of NMDA-induced activity by DTG was abolished by haloperidol but unaffected by an equimolar dose of either spiperone or thiothixine, two dopamine receptor antagonists. When mice received substance P-(1-7), NMDA-induced behaviors were initially inhibited but then potentiated. Pretreatment with haloperidol prevented both inhibitory and potentiative effects of substance P-(1-7) whereas thiothixine did not, suggesting inhibitory as well as potentiative modulation of NMDA by sigma receptor activity. Endogenous sigma 1 receptor activity may enhance NMDA receptor activity as a treatment regimen that down-regulates sigma 1 binding also inhibited responses to NMDA. In contrast, pretreatment with haloperidol just 5 min prior to challenge, which blocks both sigma 1 and sigma 2 receptor activity, increased responses to NMDA suggesting an inhibitory effect of sigma 2 receptor activity. In summary, modulation of NMDA by substance P-(1-7) appears to depend on activity at sigma sites as substance P-(1-7) mimicked the potentiative effects of DTG, while haloperidol inhibited the effects of both DTG and substance P-(1-7).

One of the most dangerous aspects of theophylline toxicity is seizures. A review of the literature suggests that current anticonvulsant therapy remains far from optimal. As it is known that some of the pharmacologic effects of theophylline occur via antagonism of the adenosine A1 receptor, we tested the hypothesis that agonists acting at the adenosine A1 receptor can inhibit seizures caused by toxic doses of theophylline in mice. Dose-response curves were constructed for the ability of theophylline to produce tonic seizures in animals pre-treated with vehicle or several adenosine A1 receptor agonists. The LD50 (95% CI) for each dose-response curve was calculated. The results of these experiments showed that pretreatment with the direct-acting adenosine A1 agonists carbamazepine and cyclohexyladenosine and the indirect-acting agonist dipyridamole each failed to inhibit the ability of theophylline to cause tonic seizures (p0.05). Failure of these drugs to protect against theophylline-induced seizures suggests these seizures are produced by other mechanisms. Based on our results, adenosine A1 agonists, such as carbamazepine, appear to offer no therapeutic benefit in the treatment of theophylline-induced seizures.

An 18-month persistence study reported nasolabial fold (NLF) improvements using a small gel-particle hyaluronic acid (SGP-HA) dermal filler lasted up to 18 months after one retreatment.[corrected] To evaluate the efficacy and persistence of SGP-HA for the correction of NLFs for up to 36 months.Subjects completing the 18-month persistence study were permitted to enroll in an 18-month extension trial. Most required second retreatments to achieve optimal correction of their NLFs. Subjects were followed for up to 36 months after their initial treatment. The primary efficacy measure was a 1-point improvement from baseline Wrinkle Severity Rating Scale (WSRS) score as determined by a blinded evaluator at different time points.The study enrolled 52 subjects. Forty subjects required a second retreatment for optimum NLF correction. Mean retreatment volume was less than 50% of the initial treatment volume. Twenty-six subjects completed the study. Blinded assessments revealed that 94% to 100% of subjects maintained WSRS scores of 1 point or more higher than baseline throughout the study.Participants in the 18-month extension of an 18-month SGP-HA persistence study continued to demonstrate improvement of NLFs up to 36 months after a second retreatment. The mean volume of SGP-HA required for optimum NLF correction decreased substantially with each retreatment. Subjects reported no treatment-related adverse events after the second retreatment.

To further explore the effects of sodium oxybate (SXB) administration on nocturnal sleep in narcolepsy patients during a double-blind, placebo-controlled, parallel group study conducted with 228 adult patients with narcolepsy/cataplexy in the United States, Canada, and Europe.Patients were withdrawn from antidepressants and sedative/hypnotics, and then randomized to receive 4.5, 6, or 9 g SXB or placebo nightly for 8 weeks. Patients receiving 6 and 9 g/night doses were titrated to their final dose in weekly 1.5 g increments, while patients receiving placebo were randomized to undergo a similar mock dose titration. The use of stimulant therapy continued unchanged. Changes in sleep architecture were measured using centrally scored nocturnal polysomnograms. Daily diaries were used to record changes in narcolepsy symptoms and adverse events.Following 8 weeks of SXB treatment, study patients demonstrated significant dose-related increases in the duration of stage 3 and 4 sleep, reaching a median increase of 52.5 minutes in patients receiving 9 g nightly. Compared to placebo-treated patients, delta power was significantly increased in all dose groups. Stage 1 sleep and the frequency of nocturnal awakenings were each significantly decreased at the 6 and 9 g/night doses. The changes in nocturnal sleep coincided with significant decreases in the severity and frequency of narcolepsy symptoms.The nightly administration of SXB to narcolepsy patients significantly impacts measures of slow wave sleep, wake after sleep onset, awakenings, total sleep time, and stage 1 sleep in a dose-related manner. The frequency and severity of narcolepsy symptoms decreased with treatment.

The ingestion of ethanol-containing products, such as cologne, perfume and after-shave, in children under six years of age is common, but serious poisoning is rarely reported. Thus, it has been recently suggested that children ingesting up to 3.5 ounces of these products may be safely observed at home as long as they remain asymptomatic. While it may be assumed that products with a significantly lower alcohol content represent a much smaller poisoning hazard, mouthwashes are a relatively frequent cause of serious poisoning in children. In the following case report, 75 milliliters of mouthwash caused hypoglycemia, coma and manifestations of tonic seizure activity. Because of the palatable nature of mouthwash, wine and liquor, it appears that children are more apt to drink large quantities, consuming dangerous amounts of ethanol. The apparent safety of cologne, perfume, and after-shave may be due to a lack of palatability as well as the irritant nature of high concentrations of ethanol. This case suggests that consumer items such as mouthwash should be packaged in child-resistant containers.

Taurine (Tau), calcium (Ca+2) and opiates each produce antinociception when injected i.t. in mice. This study was initiated to determine whether there is a common mechanism underlying their antinociceptive effects. Using the abdominal stretch assay, the antinociceptive effects of both Tau (12 nmol) and Ca+2 (72 nmol) were antagonized by i.t. TAG (4.4 nmol), a Tau antagonist, but not by i.p. injection of the opiate antagonist naloxone (5 mg/kg). The antinociceptive effects of Tau and Ca+2 correlated with their ability to inhibit the intensity of caudally-directed biting and scratching behaviors produced by i.t. NMDA or kainic acid. The inhibitory effects of both Tau and Ca+2 on the biting and scratching behaviors behaviors induced by substance P or excitatory amino acids were reversed by TAG, suggesting a common mediation by Tau. These data indicate that the antinoceptive effects of both Tau and Ca+2 appear to be mediated, at least in part, by Tau but not by the release of endogenous opioid compounds. In addition, inhibition of chemical irritant-induced nociception may be produced by a simple blockade of excitatory amino acid activity.

Background Previous studies indicate that nightly sodium oxybate administration reduces nocturnal sleep disruption in narcolepsy. The present study provided an opportunity to further characterize these sleep-related effects in patients with narcolepsy during treatment with sodium oxybate as monotherapy or in combination with modafinil. Methods This double-blind, placebo-controlled study enrolled 278 patients with narcolepsy taking modafinil 200–600 mg daily for the treatment of excessive daytime sleepiness (EDS). Following a baseline polysomnogram (PSG) and Maintenance of Wakefulness Test (MWT), patients were randomized to receive treatment with: (1) placebo, (2) sodium oxybate, (3) modafinil, or (4) sodium oxybate + modafinil. PSGs and MWTs were repeated after 4 and 8 weeks. Other efficacy measures included Epworth Sleepiness Scale scores and daily diary recordings. Results After 8 weeks, significant changes in sleep architecture among patients receiving sodium oxybate and sodium oxybate/modafinil included a median increase in Stage 3 and 4 sleep (43.5 and 24.25 min, respectively) and delta power and a median decrease in nocturnal awakenings (6.0 and 9.5, respectively). No significant changes in PSG parameters were noted in patients treated with placebo or modafinil alone. Conclusions In addition to its established efficacy for the treatment of cataplexy and EDS, nightly sodium oxybate administration significantly reduces measures of sleep disruption and significantly increases slow-wave sleep in patients with narcolepsy.

The discovery of gamma-hydroxybutyrate (GHB) over 40 years ago led to its immediate use as a general anesthetic agent. Subsequent research demonstrated that GHB is an endogenous compound in the mammalian brain and current research suggests that GHB is a probable neurotransmitter. In the United States, reports of anabolic effects lead to its misuse among body builders during the 1980's while the intoxicating properties of the drug lead to its popularization as a substance of abuse during the 1990's. GHB became associated with reports of drug-facilitated sexual assault and cases of physical dependence and withdrawal. Efforts to ban GHB caused increased use of GHB analogues and pro-drugs. Against this backdrop, GHB was being developed for the treatment of narcolepsy, leading to the approval of Xyrem (sodium oxybate) oral solution in 2002 for the treatment of cataplexy in patients with narcolepsy. A risk management program permits the safe handling and distribution of the approved product, minimizes the risk for diversion, provides professional and patient education about the risks and benefits of sodium oxybate, and includes physician and patient registries. Post-marketing surveillance indicates sodium oxybate has an acceptable safety profile and presents minimal risk for the development of physical dependence.

Ripened nightshade berries (Solanum dulcamara) are among the most commonly reported plant ingestions in Minnesota. Because of the lack of adequate information regarding the toxic qualities of S. dulcamara berries, the ingestion of even small quantities by children is usually treated conservatively with syrup of ipecac. The toxicity of S. dulcamara berries was studied by gavaging mice with a preparation of lyophilized berries, ripened and unripened, collected at various times of the year. Mice receiving unripened fruit from early in the season had gastrointestinal tissue changes consistent with solanine toxicity. Animals dosed with unripened fruit from the latter part of the year showed behavioral signs suggestive of solanine toxicity, however gastrointestinal lesions were not observed. In no case did the ripened fruit produce behavioral or histologic toxicity. Aggressive treatment of children ingesting limited amounts of ripened S. dulcamara berries appears to be unnecessary.

A double-blind, placebo-controlled sodium oxybate trial provided a unique opportunity to compare changes in cataplexy following gradual withdrawal from antidepressants in narcolepsy patients.Of 228 enrolled patients, 71 discontinued antidepressant therapy. Data from 57 patients were available for analysis: 37 patients discontinued tricyclic antidepressants (TCAs) and 20 discontinued selective serotonin reuptake inhibitors (SSRIs). The trial included a 21-day withdrawal phase followed by 18-day washout and 14-day single-blind treatment phases. Two additional weeks were permitted for withdrawal from fluoxetine due to its long half-life. Weekly cataplexy attacks were recorded throughout the trial. No historical data on the frequency of cataplexy prior to treatment with antidepressants was available.Among the patients who were and were not withdrawn from antidepressants treatment, the median frequency of baseline weekly cataplexy was similar (17.5 vs. 14.0, respectively). As expected, significant between-group differences emerged by the end of the washout period (52.04 vs. 15.25, respectively; p0.05); however, the frequency of cataplexy events became similar again by the end of the trial (16.5 vs. 17.5, respectively).Patients gradually withdrawn from antidepressants experienced a significant increase in cataplexy, but eventually returned to their baseline frequency, comparable to previously untreated control patients. Compared to SSRIs, discontinuation from TCAs was associated with a greater increase in cataplexy attacks.

Excitatory amino acids (EAAs) and substance P are believed to transmit nociceptive information in the spinal cord. As substance P NH2-terminal fragments can modulate non-NMDA EAA-mediated activity, we examined the effects of substance P fragments to ascertain whether the COOH- or NH2- terminus of substance P modulates the actions of NMDA in the spinal cord. NMDA activity was measured by the intensity of behaviors produced by NMDA (0.2 nmol) administered intrathecally in the mouse. The NMDA response was attenuated after pretreatment with either substance P (22.5 pmol, 30 min) or the NH2-terminal fragment of substance P, SP-(1– 7). Pretreatment with the COOH-terminal fragment SP-(5–11) (22.5 pmol, 30 min), a neurokinin ligand, had no effect on NMDA-induced behaviors, suggesting that the inhibitory effect of substance P is caused by the NH2-terminus. Pretreatment with D-Pro2,D-Phe7 substance P-(1–7), a SP- (1–7) antagonist, potentiated NMDA activity, suggesting a tonic inhibitory effect of the substance P NH2-terminus. Desensitization to NMDA typically develops when NMDA is injected at 2 min intervals. While pretreatment with SP-(1–7) inhibited NMDA, coadministration of SP-(1–7) (22.5 pmol), with the first of four injections of NMDA, first inhibited but then potentiated responses to each challenge with NMDA. Coadministration of the same dose of SP-(1–7) with the fourth injection of NMDA immediately potentiated the response to NMDA.(ABSTRACT TRUNCATED AT 250 WORDS)

Confusion between acetone fingernail polish removers and artificial fingernail products containing acetonitrile and N,N-dimethyl-p-toluidine has resulted in pediatric morbidity and mortality. In the present case, a 20-month-old boy drank less than one ounce of Remove Artificial Nail Remover containing 100% nitroethane. In the emergency department he displayed cyanosis and 39% methemoglobinemia. Following intravenous methylene blue, the child's methemoglobin level dropped to 5.7% and he recovered uneventfully. Toxicity from nitroethane has not previously been reported in humans. Poison centers and emergency department personnel should be alert to another nail product which may be easily confused with acetone-containing nail polish removers.

A 23-month-old boy became confused and was unable to walk thirty minutes after ingesting less than 10 mL of T36-C7, a commercial product containing 100% melaleuca oil. The child was referred to a nearby hospital. His condition improved and he was asymptomatic within 5 hours of ingestion. He was discharged to home the following day. Melaleuca oil, extracted from the Melaleuca alternifolia, contains 50-60% terpenes and related alcohols. Clinical experience with products containing melaleuca oil is limited. This case report suggests that ingestion of a modest amount of a concentrated form of this oil may produce signs of toxicity.

Even though ingestion of chewable iron preparations is much more common, treatment recommendations for iron overdose are usually based on experience with nonchewable preparations. To determine the optimal time to measure serum iron concentrations, five volunteers were given chewable iron in 5 mg/kg and 10 mg/kg doses and their serum iron concentrations monitored. Peak levels occurred at 4.2 and 4.5 hours, respectively, after ingestion, and levels drawn at 3 hours were within 90% of the peak. Naussa and headache were experienced by all volunteers, and serum iron exceeded baseline total iron binding capacity in two subjects at the 10mg/kg dose. In minor iron overdose resulting from the ingestion of chewable vitamins, serum iron concentrations measured between 3 and 7 hours (95% confidence level of peak concentrations) may be adequate in assessing the peak serum iron concentration.

Fluoroacetic and fluorocitric acid toxicity is often characterized by seizures, however the mechanism of this activity is unknown. Intrathecal (i.t.) injection of fluorocitrate in mice resulted in seizures after an average latency of 15 s, while intracerebroventricular (i.c.v.) injection produced seizures after 36.5 min, and required higher doses to achieve this effect. This indicates the probable site of fluoroacetate and fluorocitrate neurotoxicity is the spinal cord. To mimic citrate accumulation, characteristic of fluoroacetate and fluorocitrate poisoning, critic acid was injected i.t. and also found to produce seizures. The structurally unrelated compounds EDTA, EGTA, glutamic acid and lactic acid also produced seizures identical to fluorocitrate. The ability of these compounds to chelate Ca 2+ correlates well with their ability to cause seizures when administered i.t. and coadministration of calcium greatly attenuated the neurotoxicity of these compounds as well as fluoroacetate and fluorocitrate. In contrast, Ca 2+ was unable to inhibit seizures elicited by strychnine, suggesting calcium's ability to inhibit chelators of divalent cations is not due to a general anticonvulsant effect. These results suggest that changes in Ca 2+ concentration in the spinal cord may be responsible for some forms of seizure activity.