Validated Assessment Scales for the Female Asian Calf.

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.

A Validated Assessment Scale for Asian Chin Projection.

BACKGROUND: 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. OBJECTIVE: To develop and validate a Chin Projection Scale for use in the female Asian patient population. METHODS AND MATERIALS: 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). RESULTS: 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. CONCLUSION: 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.

Validation of a Photonumeric Assessment Scale for Grading the Slope of the Asian Forehead.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This photonumeric assessment scale will be useful for assessing the slope of the Asian forehead in both clinical and research settings.

Durability, Behavior, and Tolerability of 5 Hyaluronidase Products.

BACKGROUND: 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. OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: The 5 Hase products displayed a wide range of doses and times required to completely degrade the 5 HA products ranging from <2 to >16 minutes. CONCLUSION: Cosmetic practitioners should familiarize themselves with differences in HA and Hase products.

Growing evidence of the beneficial effects of a marine protein-based dietary supplement for treating hair loss.

BACKGROUND: 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.

A Six-week Low-level Laser Therapy Protocol is Effective for Reducing Waist, Hip, Thigh, and Upper Abdomen Circumference.

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/m(2) (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<0.001), and most subjects (72.2%) achieved a ≥4.5-inch decrease. Most subjects (81.0%) were Satisfied (27%) or Very Satisfied (54%) with the aesthetic results they achieved. There were no adverse events. CONCLUSION: One weekly low-level laser therapy treatment for six weeks is clinically effective for reducing waist, hip, thigh, and upper abdomen circumference and may be more effective than the previous two-week treatment protocol. ClinicalTrials.gov Identifier: NCT02109107.

Combining Microfocused Ultrasound With Botulinum Toxin and Temporary and Semi-Permanent Dermal Fillers: Safety and Current Use.

BACKGROUND: 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. OBJECTIVE: To determine the existence of any safety signals when combining MFU-V with botulinum toxin-A and/or semipermanent and temporary dermal fillers. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The Safety and Efficacy of a Sustainable Marine Extract for the Treatment of Thinning Hair: A Summary of New Clinical Research and Results from a Panel Discussion on the Problem of Thinning Hair and Current Treatments.

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.

A prospective multicenter pilot study of the safety and efficacy of microfocused ultrasound with visualization for improving lines and wrinkles of the décolleté.

BACKGROUND: A previous pilot study demonstrated microfocused ultrasound with visualization (MFU-V) to lift and tighten the décolleté produced significant and durable aesthetic improvements. OBJECTIVE: To further evaluate the safety and effectiveness of MFU-V for improving lines and wrinkles of the décolleté in a larger patient population. MATERIALS AND METHODS: Healthy women with moderate-to-severe décolleté 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 décolleté lines and wrinkles for at least the 180-day duration of the study.

Safety and efficacy of RT002, an injectable botulinum toxin type A, for treating glabellar lines: results of a phase 1/2, open-label, sequential dose-escalation study.

BACKGROUND: 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. OBJECTIVE: This phase 1/2 clinical study was designed to establish the safety of RT002 for the treatment of moderate-to-severe glabellar lines. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: RT002 is a safe and effective BoNTA product with an extended duration of action.

Safety and efficacy of microfocused ultrasound to lift, tighten, and smooth the buttocks.

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.

Persistence of nasolabial fold correction with a hyaluronic acid dermal filler with retreatment: results of an 18-month extension study.

BACKGROUND: 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. OBJECTIVE: [corrected] To evaluate the efficacy and persistence of SGP-HA for the correction of NLFs for up to 36 months. METHODS & MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

Extended-release fluvoxamine and improvements in quality of life in patients with obsessive-compulsive disorder.

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.

Relative bioavailability of sapropterin from intact and dissolved sapropterin dihydrochloride tablets and the effects of food: a randomized, open-label, crossover study in healthy adults.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by hyperphenylalaninemia in association with neurocognitive and neuromotor impairment. Sapropterin dihydrochloride (hereafter referred to as sapropterin) administered orally as dissolved tablets is approved by the US Food and Drug Administration for hyperphenylalaninemia in patients with tetrahydrobiopterin responsive PKU. OBJECTIVES: This study compared the relative oral bioavailability of sapropterin when administered as intact and dissolved tablets. It also assessed the effect of food on the oral bioavailability of sapropterin administered as intact tablets. METHODS: This was a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study in healthy male and female subjects. Subjects were randomized to receive single oral 10-mg/kg doses of sapropterin administered as dissolved tablets after a fast; as intact tablets after a fast; and as intact tablets with a high-calorie, high-fat meal. The 3 dosing periods were separated by a washout period of at least 7 days. In each dosing period, blood samples were obtained within 40 minutes before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, and 24 hours after dosing. A follow-up assessment was performed 5 to 7 days after the last dosing period. The relative bioavailability of sapropterin from the 3 dosing regimens was assessed based on C(max), AUC(0-t), and AUC(0-infinity), estimated from calculated plasma tetrahydrobiopterin concentrations using a noncompartmental model. Safety assessments included physical examinations, clinical laboratory tests, and ECGs at the beginning and end of the study. Vital signs were monitored periodically during each treatment period. RESULTS: The study enrolled 32 healthy subjects (16 men, 16 women) with a mean (SD) age of 29.2 (9.0) years, height of 172.7 (10.0) cm, weight of 73.0 (13.9) kg, and body mass index ranging from 18 to 30 kg/m(2). Twenty-three were white, 5 African American, 2 Asian/Pacific Islander, 1 Hispanic, and 1 Native American. The estimated geometric mean ratio of AUC(0-t) for intact compared with dissolved tablets under fasting conditions was 141.24% (90% CI, 122.05-163.43), and the geometric mean ratio of AUC(0-t) for intact tablets under fed compared with fasting conditions was 143.46% (90% CI, 124.22-165.69). Nine subjects (28.1%) reported a total of 20 treatment-emergent adverse events (AEs). The most frequently reported AEs were gastrointestinal disorders (6 subjects [18.8%]) and central nervous system disorders (4 [12.5%]). Eight AEs considered possibly or probably related to sapropterin were reported by 4 subjects (12.5%); these were of mild severity and gastrointestinal in nature. No severe or serious AEs or discontinuations due to AEs occurred during the study. CONCLUSIONS: Administration of sapropterin as intact tablets and with a high-calorie, high-fat meal was associated with increased drug exposure. Oral administration of sapropterin 10 mg/kg as intact tablets with or without food was generally well tolerated.

The nightly use of sodium oxybate is associated with a reduction in nocturnal sleep disruption: a double-blind, placebo-controlled study in patients with narcolepsy.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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 nightly administration of sodium oxybate results in significant reduction in the nocturnal sleep disruption of patients with narcolepsy.

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.

Exacerbation of cataplexy following gradual withdrawal of antidepressants: manifestation of probable protracted rebound cataplexy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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; p<0.05); however, the frequency of cataplexy events became similar again by the end of the trial (16.5 vs. 17.5, respectively). CONCLUSIONS: 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.

The clinical development of gamma-hydroxybutyrate (GHB).

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.

The Xyrem risk management program.

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.