Dose-escalation study of octanoic acid in patients with essential tremor.

BACKGROUND: Recently, 1-octanol has been shown to have efficacy in treating patients with essential tremor (ET). The primary metabolite of 1-octanol is octanoic acid (OA), which is now thought to be the active substance that mediates tremor suppression. Our aim was to describe the maximum tolerated dose (MTD) of oral OA in patients with ET and assess the pharmacokinetics (PK) and pharmacodynamics (PD) profile of OA. METHODS: The MTD was studied using an open-label, single-ascending 3 + 3 dose-escalation design. Predefined single doses ranged from 8 to 128 mg/kg, with grade 2 adverse events (AEs) defined as dose-limiting toxicity. Tremor was assessed using accelerometry, digital spiral analysis, and a standard clinical rating scale at baseline and up to 600 minutes after intake. Safety assessments and PK sampling were also performed. RESULTS: Dose-limiting toxicity was not reached. The most frequent AE was mild abdominal discomfort. Exposure (AUC) increased linearly with the dose. Secondary efficacy measures suggested a dose-dependent reduction of tremor. Accordingly, a single unified PK/PD model with an effect compartment and sigmoid maximum effect (Emax) response could be built that accounted well for the time profiles of plasma concentrations as well as effects on tremor severity across the 5 dose levels. CONCLUSION: Although our trial did not reach an MTD, a dose-dependent effect was demonstrated in the PK/PD model as well as in secondary efficacy outcomes. Future studies are needed to explore the safety in higher dose ranges and to confirm dose-dependent efficacy in a placebo-controlled design. TRIAL REGISTRATION: Clinicaltrials.gov NCT01468948FUNDING. NINDS Intramural Research Program; TG Therapeutics Inc.

Octanoic acid in alcohol-responsive essential tremor: a randomized controlled study.

OBJECTIVE: To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET). METHODS: We conducted a double-blind, placebo-controlled, crossover, phase I/II clinical trial evaluating the effect of 4 mg/kg OA in 19 subjects with ET. The primary outcome was accelerometric postural tremor power of the dominant hand 80 minutes after administration. Secondary outcomes included digital spiral analysis, pharmacokinetic sampling, as well as safety measures. RESULTS: OA was safe and well tolerated. Nonserious adverse events were mild (Common Terminology Criteria for Adverse Events grade 1) and equally present after OA and placebo. At the primary outcome, OA effects were not different from placebo. Secondary outcome analyses of digital spiral analysis, comparison across the entire time course in weighted and nonweighted accelerometry, as well as nondominant hand tremor power did not show a benefit of OA over placebo. The analysis of individual time points showed that OA improved tremor at 300 minutes (dominant hand, F = 5.49, p = 0.032 vs placebo), with a maximum benefit at 180 minutes after OA (both hands, F = 6.1, p = 0.025). CONCLUSIONS: Although the effects of OA and placebo at the primary outcome were not different, secondary outcome measures suggest superiority of OA in reducing tremor at later time points, warranting further trials at higher dose levels. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a single 4-mg/kg dose of OA is not effective in reducing postural tremor in patients with ET at a primary outcome of 80 minutes, but is effective for a secondary outcome after 180 minutes.

An open-label, single-dose, crossover study of the pharmacokinetics and metabolism of two oral formulations of 1-octanol in patients with essential tremor.

Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer-chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor-suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1-64 mg/kg; n = 4), and (part B) a fixed dose (64 mg/kg; n = 10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg.Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was assessed using spirography, whereas safety was assessed with electrocardiograms, vital signs, adverse effects surveys, and an intoxication assessment. Plasma concentrations of 1-octanol were detectable at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6 minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement. These findings provide preliminary evidence for a new class of compound that may be effective in the treatment of ET.

The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants.

BACKGROUND: The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection. METHODOLOGY: A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit. FINDINGS: Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation. CONCLUSIONS: Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00101374.

Placebo-controlled study of intravenous magnesium supplementation during large-volume leukapheresis in healthy allogeneic donors.

BACKGROUND: Marked decreases in ionized magnesium (iMg) levels occur during large-volume leukapheresis (LVL); however, the effect of intravenous (IV) magnesium supplementation in this setting has not been carefully studied. STUDY DESIGN AND METHODS: Thirty healthy allogeneic peripheral blood progenitor cell donors receiving citrate anticoagulant with IV calcium prophylaxis were randomized to receive either IV magnesium (0.2 mg Mg per mL acid citrate dextrose-A) or placebo during LVL, with a double-blind design. RESULTS: Thirty subjects underwent 75 LVL pro- cedures, 37 with magnesium and 38 with placebo. Group characteristics were similar for sex, weight, citrate infusion rate (1.36 mg/kg/min vs. 1.37 mg/kg/min), and volume processed (16 L vs. 17 L). Serum iMg levels remained within the reference range with magnesium supplementation, but decreased 39+/-11 percent below baseline (p<10(-10)) after placebo, with greater decreases after consecutive procedures. Subjects receiving magnesium had more vigorous parathyroid hormone responses and higher glucose levels and also tended to have higher serum potassium and ionized calcium levels. Mild paresthesias, coldness, and nausea occurred in 28, 20, and 7 percent of donors, respectively, with no significant differences between groups. Severe symptoms (chest tightness) occurred in only one subject receiving placebo. CONCLUSION: IV magnesium supplementation exerts a significant impact on serum magnesium levels, but does not reduce the frequency or severity of the relatively mild citrate-related effects observed in LVL performed with continuous IV calcium prophylaxis.

Randomized placebo-controlled study of oral calcium carbonate administration in plateletpheresis: I. Associations with donor symptoms.

BACKGROUND: The effect of oral calcium (Ca) supplements in preventing citrate-induced symptoms during plateletpheresis was evaluated in a randomized, blinded, placebo-controlled trial. STUDY DESIGN AND METHODS: Twenty-three donors (12 men, 11 women) underwent four plateletpheresis procedures each, ingesting either 1 or 2 g of oral Ca carbonate or an equivalent placebo 30 minutes before donation. Ten of these subjects subsequently ingested 4 g of open-label Ca before a fifth procedure. All procedures were conducted at the same citrate infusion rate (1.5 mg/kg/min) for 90 minutes. RESULTS: Ingestion of 2 g of oral Ca resulted in a significant reduction in the severity of paresthesias and a significant, though modest, increase in serum ionized calcium (iCa), but no significant improvement in total symptom scores, compared to placebo. Minimal effects were seen with the 1-g dose. The two factors most highly correlated with development of severe symptoms were decreased levels of iCa and ionized magnesium (iMg) at 30 minutes into apheresis. Lower preapheresis serum albumin, creatinine, vitamin D, iMg, and total Mg concentrations were also significantly associated with symptoms. Women experienced more frequent and severe symptoms than men, however, gender was not associated with symptoms after adjustment for lower serum albumin, creatinine, and Mg levels. Ingestion of 4 g of Ca offered no improvement in symptoms or iCa levels compared with the 2-g dose. CONCLUSION: Prophylactic oral Ca was associated with modest improvements in citrate-induced symptoms and laboratory parameters. Baseline albumin and Mg levels were strongly predictive of the development of symptoms. In donors with a prior history of uncomfortable citrate-related effects, a 2-g oral Ca dose before apheresis is recommended.

Itraconazole to prevent fungal infections in chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease is a rare disorder in which the phagocytes fail to produce hydrogen peroxide. The patients are predisposed to bacterial and fungal infections. Prophylactic antibiotics and interferon gamma have reduced bacterial infections, but there is also the danger of life-threatening fungal infections. We assessed the efficacy of itraconazole as prophylaxis against serious fungal infections in chronic granulomatous disease. METHODS: Thirty-nine patients at least 5 years old (6 female and 33 male; mean age, 14.9 years) were enrolled in a randomized, double-blind, placebo-controlled study. After the initially assigned treatment, each patient alternated between itraconazole and placebo annually. Patients 13 years of age or older and all patients weighing at least 50 kg received a single dose of 200 mg of itraconazole per day; those less than 13 years old or weighing less than 50 kg received a single dose of 100 mg per day. The primary end point was severe fungal infection, as determined by histologic results or culture. RESULTS: One patient (who had not been compliant with the treatment) had a serious fungal infection while receiving itraconazole, as compared with seven who had a serious fungal infection while receiving placebo (P=0.10). No patient receiving itraconazole but five patients receiving placebo had a superficial fungal infection. No serious toxic effects were noted, although one patient had a rash and another had elevated results on liver-function tests; both of these effects resolved with the discontinuation of itraconazole. CONCLUSIONS: Itraconazole prophylaxis appears to be an effective and well-tolerated treatment that reduces the frequency of fungal infections in chronic granulomatous disease, but monitoring for long-term toxic effects is warranted.

Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics.

We investigated the clinical characteristics and treatment of patients with a distinctive triad of acute infusion-related reactions (AIRRs) to liposomal amphotericin B (L-AMB) via single-center and multicenter analyses. AIRRs occurred alone or in combination within 1 of 3 symptom complexes: (1) chest pain, dyspnea, and hypoxia; (2) severe abdomen, flank, or leg pain; and (3) flushing and urticaria. The frequency of AIRRs in the single-center analysis increased over time. Most AIRRs (86%) occurred within the first 5 min of infusion. All patients experienced rapid resolution of symptoms after intravenous diphenhydramine was administered. The multicenter analysis demonstrated a mean overall frequency of 20% (range, 0%-100%) of AIRRs among 64 centers. A triad of severe AIRRs to L-AMB may occur in some centers; most of these reactions may be effectively managed by diphenhydramine administration and interruption of L-AMB infusion.