Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and Cmax and was slowly eliminated (mean t1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues.

Difluprednate ophthalmic emulsion 0.05% (Durezol) administered two times daily for managing ocular inflammation and pain following cataract surgery.

OBJECTIVE: To evaluate the efficacy and safety of twice-daily difluprednate ophthalmic emulsion 0.05% (Durezol(®)) versus placebo administered before surgery for managing inflammation and pain following cataract extraction. METHODS: Eligible subjects (N = 121) were randomized 2:1 to topical treatment with 1 drop difluprednate or placebo administered twice daily for 16 days, followed by a 14-day tapering period. Dosing was initiated 24 hours before unilateral ocular surgery. Clinical signs of inflammation (anterior chamber [AC] cell and flare grade, bulbar conjunctival injection, ciliary injection, corneal edema, and chemosis), ocular pain/discomfort, intraocular pressure (IOP), and adverse events were assessed. RESULTS: Clearing of inflammation on day 14 (primary endpoint), defined as an AC cell grade of 0 (≤5 cells) and a flare grade of 0 (complete absence), was achieved in a significantly greater percentage of subjects treated with difluprednate, compared with placebo (74.7% vs 42.5%; P = 0.0006). A significantly greater percentage of difluprednate-treated subjects were free of ocular pain/discomfort on day 14 than placebo-treated subjects (64.6% vs 30.0%; P = 0.0004). Three subjects (3.7%) in the difluprednate group had a clinically significant IOP rise (defined as ≥21 mmHg and a change from baseline ≥10 mmHg at same visit). CONCLUSIONS: Difluprednate, administered 2 times daily starting 24 hours before cataract surgery, was highly effective for managing ocular inflammation and relieving pain and discomfort postoperatively. Difluprednate was well tolerated and provides a convenient twice-daily option for managing postoperative ocular inflammation.

High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study.

OBJECTIVE: Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low-dose colchicine (abbreviated at 1 hour) and high-dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study compared self-administered low-dose colchicine (1.8 mg total over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was > or = 50% pain reduction at 24 hours without rescue medication. RESULTS: There were 184 patients in the intent-to-treat analysis. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (P = 0.005 and P = 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high-dose group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low-dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7-3.2). High-dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low-dose colchicine or placebo. With high-dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9-56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8-4.8]), none had severe diarrhea, and none had vomiting. CONCLUSION: Low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose colchicine, with a safety profile indistinguishable from that of placebo.

Two-year multicenter, randomized, double-masked, placebo-controlled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia.

PURPOSE: To evaluate if the safety and efficacy of the relatively selective M1-antagonist, pirenzepine, in slowing the progression of myopia in children is sustained over a 2-year period. METHODS: This was a multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial. Enrolled were children aged 8 to 12 years, with entry spherical equivalent refractive error of -0.75 to -4.00 D and astigmatism

Lidocaine patch 5 for carpal tunnel syndrome: how it compares with injections: a pilot study.

OBJECTIVES: A standard treatment option for mild-to-moderate carpal tunnel syndrome (CTS) is a local injection of anesthetic-corticosteroid, but this can be painful and may cause complications. This pilot clinical trial was designed to compare the safety and efficacy of daily applications of the lidocaine patch 5% to that of a single injection of 0.5 cc lidocaine 1% plus methylprednisolone acetate (Depo-Medrol) 40 mg. METHODS: In this randomized, parallel-group, open-label, single-center, active-controlled, prospective pilot study, participants aged 18-75 years with clinical/electrodiagnostic evidence of CTS were randomized to receive the lidocaine patch 5% or 1 injection of 0.5 cc lidocaine 1% plus Depo-Medrol 40 mg. Outcome assessments included the Brief Pain Inventory (measuring pain intensity, relief, and interference with quality of life, Patient and Global Clinical Impression of Improvement, Global Assessment of Treatment Satisfaction, and safety. RESULTS: Baseline characteristics of the 40 patients randomized to treatment with the lidocaine patch 5% (n=20) or injection (n=20) were similar between groups. After 4 weeks of treatment, patients in both groups reported significant changes (P<.05) in worst pain, average pain, and pain "right now." Composite interference scores, which are measures of how much patients' pain interfered with quality of life, also significantly improved in both treatment groups (patch, -13.9; injection, -16.7; P<.001 vs baseline for both groups). Eighty percent of patients in the lidocaine patch group and 59% of patients who received the injection reported being "satisfied" or "very satisfied," while investigators reported improvement in 88% of patients using the lidocaine patch and in 74% of those who received the injection. Both treatments were well tolerated, with treatment-related adverse events (AEs) reported in 3 patients in each group (15%). No systemic treatment-related AEs were observed with the lidocaine patch 5%. CONCLUSIONS: This pilot trial demonstrated that the lidocaine patch 5% was efficacious in reducing pain associated with CTS and was well tolerated. The lidocaine patch 5% may offer patients with CTS effective, noninvasive treatment for the management of their symptoms. Further controlled trials are warranted.

A comparison of the lidocaine patch 5% vs naproxen 500 mg twice daily for the relief of pain associated with carpal tunnel syndrome: a 6-week, randomized, parallel-group study.

OBJECTIVES: Carpal tunnel syndrome (CTS) is a common entrapment neuropathy caused by median nerve compression. This pilot clinical trial was designed to compare the safety and effectiveness of the lidocaine patch 5% to that of naproxen 500 mg twice daily for the treatment of neuropathic pain associated with CTS. METHODS: In this 6-week, randomized, parallel-group, open-label, multicenter study, participants from 2 practice sites, aged 18 to 75 years with clinical/electrodiagnostic evidence of CTS, were randomized to receive up to 3 lidocaine 5% patches every 24 hours or naproxen 500 mg twice daily for 6 weeks. Outcome assessments included mean changes between baseline and Week 6 average pain intensity (Brief Pain Inventory [BPI]: Question 5, Average Pain Intensity [API]), an Investigator Clinical Global Impression of Improvement (CGI-I) over the course of the treatment period and a comparison of patient satisfaction (Clinical Global Assessment of Treatment [CGAT]). RESULTS: One hundred patients were randomized in this study, 52 in the lidocaine patch 5% group and 48 in the naproxen 500 mg twice daily group. Significant reductions in API scores were observed between baseline and Week 6 for both lidocaine patch 5% (P < .0001) and naproxen 500 mg twice daily (P = .0004); however, there were no statistically significant differences between treatments (P = .083). There was a significant (P = .016) difference in the CGI-I for lidocaine patch 5% (51.1%) compared with naproxen 500 mg twice daily (24.3%). Whereas 71.8% of the lidocaine patch 5% patients reported being "satisfied" to "very satisfied" with the treatment, only 63.2% of naproxen 500 mg twice daily patients reported likewise, although the difference was not statistically significant. Both treatments were well tolerated. Two patients reported treatment-related adverse events in the lidocaine patch 5% group and 6 in the naproxen 500 mg twice daily group, all of which were considered mild or moderate in severity. CONCLUSIONS: This study demonstrates that the lidocaine patch 5% is effective in significantly relieving the pain associated with CTS and is well tolerated. The patch may offer patients an effective, nonsystemic, noninvasive treatment for the management of their symptoms. Further controlled studies are warranted.

A tolerability study of pirenzepine ophthalmic gel in myopic children.

PURPOSE: The objective of this study was to determine the safety and tolerability of pirenzepine ophthalmic gel (PIR) and the magnitude of mydriatic and accommodative effects in myopic children. METHODS: This was a placebo-controlled, parallel double-masked study of unequal (4:1) randomization. Children were randomized to receive 0.5% PIR, b.i.d., or vehicle (placebo) for one week, then titrated to 1% PIR for one week, then 2% PIR for two weeks, and then for an additional 11 months. Enrolled were 26 normal healthy children, 9-12 years old, with myopia (-0.75 to -3 D) and minimal astigmatism (< or =1 D, O.U.). RESULTS: Three of the 26 subjects (all in PIR group) did not complete one year of the study: one child at day 8 who inadvertently received 2.0% PIR as the first concentration, due to accommodative insufficiency, one child for follicular conjunctivitis at 9 months, and one child for administrative reasons at month 1. Other than the child discontinued at day 8, all patients were titrated up to the highest concentration of PIR evaluated. When measured 1 hour after instillation of PIR 0.5%, there was a mean mydriatic effect of less than 1 mm compared to vehicle in either bright or dim light. With increasing concentrations of PIR, this effect became numerically larger, although still remained less than 1 mm in either bright or dim light. Measured approximately 12 hours after instillation, there was little mydriasis within each group (relative to baseline) or between treatments. Similar mild PIR effects were seen on accommodative amplitude. In general, the adverse events reported were mild or moderate in severity, resolved rapidly, and were of the nature and incidence to be expected in a study of a topical anti-muscarinic gel in children of this age. CONCLUSION: The promising efficacy results and acceptable safety profile justifies proceeding with additional clinical trials to evaluate efficacy and further characterize the safety of pirenzepine in a larger patient population.

Change in intraocular pressure during long-term use of loteprednol etabonate.

PURPOSE: Loteprednol etabonate is a novel site-active corticosteroid synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. In double-masked studies, loteprednol etabonate was effective in the treatment of giant papillary conjunctivitis, seasonal allergic conjunctivitis, postoperative inflammation, and uveitis. The objective of this analysis was to determine the incidence of clinically significant elevations in intraocular pressure (IOP) with long-term use of loteprednol etabonate. PATIENTS AND METHODS: All subjects (healthy volunteers or patients with inflammation or allergy) in all sponsored loteprednol etabonate studies in the United States were evaluated. A clinically significant elevation in IOP was defined as > or = 10 mmHg at any visit, and long-term use was defined as > or = 28 days. Of the 2,210 subjects, 1,648 were treated for 28 days or longer with loteprednol etabonate (0.2% or 0.5%), prednisolone acetate 1%, or vehicle. RESULTS: IOP elevation > or = 10 mmHg occurred in 1.7% (15/901) of patients taking long-term loteprednol etabonate, 0.5% (3/583) of those taking vehicle, and 6.7% (11/164) of those taking prednisolone acetate. Excluding patients who wore contact lenses, the incidence was 0.6% (4/624), 1.0% (3/304), and 6.7% (11/164) for loteprednol etabonate, vehicle, and prednisolone acetate, respectively. The incidence of IOP elevations with 0.2% loteprednol etabonate was 0.8% (1/133), similar to that for vehicle (0.7%, 1/135). CONCLUSION: The results of this analysis in a large population of subjects undergoing long-term therapy and of a previously published controlled, double-masked study in corticosteroid responders suggest that loteprednol etabonate has less propensity to cause clinically significant elevations in IOP than prednisolone acetate.

Association of leptospiral seroreactivity and breed with uveitis and blindness in horses: 372 cases (1986-1993).

Recurrent uveitis, a leading cause of blindness in horses, often develops as a sequela to systemic leptospirosis. Over a 7-year period, 63 of 112 (56%) horses with uveitis were seropositive for Leptospira interrogans serovar pomona, but only 23 of 260 (9%) horses without uveitis were seropositive. Odds-ratio analysis revealed that seropositive horses were 13.2 times more likely to have uveitis than were seronegative horses. Of the 63 seropositive horses with uveitis, 59% developed blindness, compared with only 24% in the 49 seronegative horses with uveitis that lost vision in 1 or both eyes during the same period. Odds-ratio analysis revealed that seropositive horses with uveitis were 4.4 times more likely to lose vision than were seronegative horses with uveitis. Of the 112 horses with uveitis, 28 (25%) were Appaloosas, compared with only 10 of the 260 (4%) horses without uveitis (odds ratio, 8.3). In addition, 19 of the 28 (68%) Appaloosas with uveitis developed blindness, compared with only 30 of the 84 (36%) non-Appaloosas with uveitis that lost vision in 1 or both eyes (odds ratio, 3.8). This field study therefore confirmed a strong positive relationship between uveitis and leptospiral seroreactivity in horses. Furthermore, the data suggested that seropositive horses with uveitis were at increased risk of losing vision, compared with that in seronegative horses with uveitis, and that Appaloosas were at increased risk of developing uveitis and associated blindness, compared with that in non-Appaloosas.

Tolerance of intravitreal povidone-iodine in rabbit eyes.

Povidone-iodine is frequently instilled on to the conjunctival surface prior to intraocular surgery in order to prevent septic endophthalmitis. A small amount of povidone-iodine is inevitably introduced into the eye when it is used in this manner. The toxicity of intravitreal povidone-iodine was assessed in rabbit eyes by injecting 0.1 ml of povidone-iodine in concentrations of 0.05%, 0.5% and 5% into the vitreous cavity. The injected eyes were evaluated by clinical examination, anterior segment and fundus photography, endothelial cell counts, electroretinography and histopathology. Compared to control eyes, no changes were observed in all 6 eyes injected with 0.1 ml of 0.05% povidone-iodine solution. 9 of 10 eyes tolerated a concentration of 0.5% with no detectable adverse changes. One eye developed a temporary mild iritis and mild suppression of the ERG. Intra-retinal hemorrhages, edema, arteriolar narrowing and retinal edema were seen one week following injection. Mild retinal necrosis of the same area was seen on histology. All 4 eyes injected with 5% povidone-iodine developed temporary hypotony and iridocyclitis. A dense cataract developed in all eyes. Full thickness retinal necrosis and a profound lasting reduction in the ERG was produced in all of these eyes. No corneal epithelial or endothelial changes were observed in any eye in this series. Low concentrations of intravitreal povidone-iodine likely to be produced by instillation prior to surgery are tolerated by rabbit eyes. The concentrations tolerated by the studied eyes are near reported bactericidal levels.

Effect of in vitro ultraviolet radiation on the binding capacity of anti-DNA and DNA in systemic lupus erythematosus.

The in vitro effects of various doses of ultra violet A (UVA) or UVB irradiation on DNA or anti-DNA as measured by their subsequent binding to anti-DNA or DNA were examined. Sera from 12 patients with active lupus were studied. UVA irradiation at 20-240 J/m2 or UVB irradiation at 2-24 J/m2 did not affect DNA or anti-DNA binding to anti-DNA or DNA, respectively. Modulation of the UV effect on DNA and anti-DNA by adding methylprednisolone, hydroxychloroquine and indomethacin at 10(-6) M did not alter the UV effect. UV light does not exert its effect directly on the binding of anti-DNA to DNA.

Distribution of incorporated [3H]uridine in mouse brain as a function of route of administration.

The effect of injection by intracranial and systemic routes on the localization of [3H]uridine incorporated into RNA of mouse brain was quantitated autoradiographically. The pattern of labeled RNA 45 min after intraventricular or intracisternal injection was highly variable throughout the brain, and activity was localized in structures adjacent to the ventricles or subarachnoid space. The amount incorporated was inversely related to distance from these cerebrospinal fluid compartments with little incorporation observed at distances greater than 200 microns. In contrast to intracranial administration, intrapleural and subcutaneous routes yielded a more homogeneous distribution of incorporated uridine throughout the brain. Regional differences in the autoradiographic pattern following systemic administration were correlated with regional differences in cell density. The results clearly indicate that injection route is a potent factor affecting the localization of agents used to study brain.

Oxygen dependence of damage by 435 nm light in cultured retinal epithelium.

Light damages the cultured bovine retinal epithelium at about the same intensities as those effective in the primate retina, in vivo. Also as in vivo, blue light (457.9 nm) is substantially more damaging than longer wavelengths of the visible spectrum. Experiments were performed to test whether this damage by light is mediated by a photodynamic reaction. Primary confluent monolayer cultures of the bovine retinal epithelium were exposed to 435 nm light for 120 minutes, during which time the oxygen content in the gas phase of the exposure chamber was maintained at a predetermined value. Prior to and after light exposure the cultures were aerated by 20% oxygen. The normal growth medium (Eagle's MEM + 10% fetal calf serum) was used during exposure. Light microscopic and EM examination 24 hours after exposure showed that changes indicating cell death were enhanced by a factor of 10 when exposures were conducted in an atmosphere of 95% oxygen instead of 20% oxygen. No damage at intensities up to 50 mw/sq.cm. was observed with a 0% oxygen atmosphere. These effects were the same when a saline, bicarbonate buffered medium was used during exposure. It is concluded that short wavelength light damage to the retinal epithelium is caused by a photodynamic reaction, i.e. a photosensitized aerobic oxidation. This is the first time that the mechanism of blue light damage on a retinal tissue has been established.(ABSTRACT TRUNCATED AT 250 WORDS)

Diurnal variations in the analgesic effectiveness of morphine in mice.

Response to thermal stimulation and the analgesic effectiveness of morphine during various phases of the diurnal cycle were assessed by the hotplate method. Saline treated controls exhibited shortest reaction times during the last quarter of the light-phase and first quarter of the dark phase. Longest reaction times were recorded during the last quarter of the dark phase. Doses of 4, 8, 16, and 32 mg/kg of morphine was administered IP at the peak and trough of the pain sensitivity rhythm. The ED50 (95% C.L.) during the last quarter of the light phase was found to be 14.60 (10.6-20.0) mg/kg while during the last quarter of the dark phase the ED50 was found to be 5.85 (4.5-7.7) mg/kg. In a second experiment, independent groups of ten mice each were injected SC with 8 mg/kg of morphine at three hr intervals over a 48 hr test session. Peak analgesic activity was obtained in the group injected during the last quarter of the dark phase while minimal analgesic effectiveness was obtained during the third quarter of the light phase. Central administration of morphine via the intraventricular route yielded the same relationship, i.e., maximal analgesic effectiveness during the last quarter of the dark phase.