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Deutetrabenazine (Austedo) is indicated in adults for chorea associated with Huntington disease and tardive dyskinesia. Escalating deutetrabenazine doses were administered to healthy volunteers who were cytochrome P450 2D6 extensive/intermediate metabolizers (EMs) or poor metabolizers (PMs) to determine pharmacokinetic exposure of parent drug and active metabolites (α-dihydrotetrabenazine [α-HTBZ] and β-dihydrotetrabenazine [β-HTBZ]), and collect corresponding electrocardiograms (ECGs) for evaluation of the cardiodynamic effect using concentration-QTc (C-QTc) modeling. Participants (12 EMs, 24 PMs) received placebo or single doses of deutetrabenazine (24, 48, and 72 mg) to achieve plasma concentrations exceeding therapeutic range in both cohorts. Pharmacokinetic samples were obtained over 72 hours after dosing and were time matched with 12-lead ECGs extracted from continuous ECG recordings. C-QTc analysis, using linear mixed-effects modeling and model selection procedure, characterized the relationship between plasma concentrations of deutetrabenazine, deuterated α-HTBZ and β-HTBZ, and the change from baseline in QT interval corrected using Fridericia's formula. Deutetrabenazine exhibited linear kinetics, and a C-QTc model with deuterated α-HTBZ and β-HTBZ was selected to best describe the C-QTc relationship in pooled EM and PM data. This model predicted a placebo-corrected Fridericia corrected QT interval prolongation higher than 10 milliseconds can be excluded at concentrations associated with the maximum recommended doses in both populations. Adverse events increased with higher exposure as reflected by the higher event number in the PM cohort receiving 48 and 72 mg doses. No subject discontinued due to cardiac-related adverse events and no clinically relevant ECG findings were reported. Thus, this study found that deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 EMs or PMs.

Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α‐dihydrotetrabenazine (α‐HTBZ) and β‐dihydrotetrabenazine (β‐HTBZ). One study was an open‐label 2‐part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open‐label 5‐way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high‐fat meal. Both studies confirmed longer half‐lives for active metabolites and lower peak‐to‐trough fluctuations for the sum of the metabolites (total [α+β]‐HTBZ) following deutetrabenazine compared with tetrabenazine (3‐ to 4‐fold and 11‐fold, respectively) in steady‐state conditions. Deutetrabenazine doses estimated to provide total (α+β)‐HTBZ exposure comparable to tetrabenazine 25 mg were 11.4‐13.2 mg. Food had no effect on exposure to total (α+β)‐HTBZ, as measured by AUC. Although the total (α+β)‐HTBZ Cmax of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.

Laquinimod, a neuroimmunomodulator, is extensively metabolized by cytochrome P450 (CYP) 3A4, and modulations of CYP3A4 activity may lead to alterations in the pharmacokinetics and/or clinical effects of laquinimod. To determine the drug-drug interaction potential of laquinimod with CYP3A inhibitors and inducers, interaction assessments were conducted in healthy volunteers using single-dose administration of laquinimod before and after multiple dosing of CYP3A inhibitors (ketoconazole, fluconazole, and cimetidine) or a CYP3A4 inducer (rifampin). For ketoconazole, subjects (n = 14) received laquinimod 0.6 mg following 1 day of ketoconazole (400 mg daily) pretreatment, a single concomitant dose, and 28 additional days. For fluconazole, subjects (n = 14) received laquinimod 0.6 mg after a single fluconazole dose of 400 mg followed by 200-mg daily fluconazole administration for 20 additional days. For cimetidine, subjects (n = 14) received laquinimod 0.6 mg following 1 day of cimetidine (800 mg twice daily) pretreatment, a single concomitant dose, and 21 additional days. For rifampin, subjects (n = 14) received laquinimod 0.6 mg following 9 days of rifampin (600 mg daily) pretreatment, a single concomitant dose, and 12 additional days. Coadministration of laquinimod with CYP3A inhibitors, ketoconazole, fluconazole, and cimetidine increased laquinimod area under the plasma concentration-time curve from time zero to infinity by approximately 3.1-, 2.5-, and 1.1-fold, respectively. Coadministration of laquinimod with rifampin decreased laquinimod area under the plasma concentration-time curve from time zero to infinity by 5-fold. These results indicate that coadministration of laquinimod with moderate to strong inhibitors of CYP3A or strong inducers of CYP3A may give rise to significant pharmacokinetic drug interactions.

Previous studies have demonstrated the feasibility and promise of wearable sensors as objective measures of motor impairment in Parkinson disease and essential tremor. However, there are few published studies that have examined such an application in Huntington disease (HD). This report provides an evaluation of the potential to objectively quantify chorea in HD patients using wearable sensor data. Data were derived from a substudy of the phase 2 Open-PRIDE-HD study, where 17 patients were screened and 15 patients enrolled in the substudy and ultimately 10 patients provided sufficient wearable sensor data. The substudy was designed to provide high-resolution data to inform design of predictive algorithms for chorea quantification. During the entire course of the 6-month study, in addition to chorea ratings from 18 in-clinic assessments, 890 home assessments, and 1,388 responses to daily reminders, 33,000 h of high-resolution accelerometer data were captured continuously from wearable smartwatches and smartphones. Despite its limited sample size, our study demonstrates that arm chorea can be characterized using accelerometer data during static assessments. Nonetheless, the small sample size limits the generalizability of the model. The sensor-based model can quantify the chorea level with high correlation to the chorea severity reported by both clinicians and patients. In addition, our analysis shows that the chorea digital signature varies between patients. This work suggests that digital wearable sensors have the potential to support clinical development of medications in patients with movement disorders, such as chorea. However, additional data would be needed from a larger number of HD patients with a full range of chorea severity (none to severe) with and without intervention to validate this potentially predictive technology.

Background Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study’s results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies. Methods Initial application of the adult model suggested that a 75 mg dose in pediatric patients would match exposures determined safe and efficacious in adults; thus, in the phase 1 study, 15 patients, aged 6–11 years and weighing 17–45 kg received a single subcutaneous 75 mg fremanezumab dose. The sparse pharmacokinetic data collected were used to refine the adult model and simulate concentration-time profiles for monthly subcutaneous doses (60 to 225 mg) in a virtual pediatric population. Results In the phase 1 pediatric study, the safety profile was similar to that of adults. A two-compartment model with first-order absorption and elimination and body weight effects on clearance and central volume was found to adequately describe the pediatric pharmacokinetic data. Conclusions Using exposure matching to the effective adult fremanezumab dose (225 mg subcutaneous monthly), modeling and simulations predict recommended dose of 120 mg in pediatric patients weighing

Fremanezumab (AJOVY; Teva Pharmaceutical Industries Ltd, Netanya, Israel), approved for the preventive treatment of migraine, is available as a subcutaneous injection either once a month or once every 3 months using an autoinjector or a prefilled syringe. The present study evaluated the pharmacokinetic (PK) bioequivalence of a single subcutaneous injection of fremanezumab 225 mg administered using an autoinjector compared to a prefilled syringe in healthy volunteers. Blood samples for PK and antidrug antibodies were collected before and after dosing. Safety and tolerability assessments included physical examinations, adverse event reporting, laboratory evaluations, and immunogenicity. Following single‐dose administration, the mean concentration‐time profiles for the 2 treatment groups (autoinjector, n = 106; and prefilled syringe, n = 110) were similar. The point estimates for the back‐transformed ratio (autoinjector/prefilled syringe) of geometric least squares means of maximum plasma concentration, area under the plasma concentration–time curve from time 0 to the time of the last measurable drug concentration, and area under the plasma concentration–time curve from time 0 extrapolated to infinity were 1.03, 1.04, and 1.05, respectively, with the 90% confidence intervals entirely contained within bioequivalence margins of 0.8 to 1.25. For both groups, median time to maximum observed concentration was 5 days and mean terminal elimination half‐life was approximately 29 days. Treatment‐related adverse events were reported by 39 (36%) subjects in the autoinjector group and 26 (24%) in the prefilled syringe group, and the majority were nonserious injection site reactions. The incidence of treatment‐emergent antidrug antibody response was low and evenly distributed between the autoinjector (n = 3; 3%) and prefilled syringe (n = 4; 4%) groups. These results indicate that the fremanezumab autoinjector presentation provides an easy‐to‐use bioequivalent PK profile with a similar safety and tolerability profile to that of the prefilled syringe.

ObjectiveTo evaluate the effect of fremanezumab on the functional status on headache-free days in phase 2 episodic migraine (EM) and chronic migraine (CM) studies.MethodsFunctional status data were collected prospectively via the electronic headache diary on all headache-free days by patients answering questions regarding work/school/household chore performance, speed of work completion, concentration, and feeling of fatigue. Individuals with EM receiving monthly doses of fremanezumab 225 mg (n = 96) or 675 mg (n = 97) or placebo (n = 104) were compared. Individuals with CM receiving fremanezumab 675 mg followed by monthly 225 mg (n = 88) and 900 mg (n = 86) were also independently compared to those receiving placebo (n = 89).ResultsIn patients with EM, compared to patients receiving placebo, those receiving fremanezumab experienced an increased number of headache-free days with normal function in work/school/household chore performance and concentration/mental fatigue measures compared to their baseline over the entire treatment period (allp< 0.005). An increased number of headache-free days with normal functional performance for some measures was also found in the CM group in those treated with fremanezumab.ConclusionThere was an increased number of headache-free days with normal functional performance on all measures for the patients with EM and some measures for patients with CM in the fremanezumab-treated groups. Further research is required to confirm these findings in a prospective study and to clarify the underlying mechanism(s).ClinicalTrials.gov identifier:NCT02025556 andNCT02021773.Classification of evidenceThis study provides Class II evidence that for patients with migraine, fremanezumab increases normal functional performance on headache-free days.

AIMS SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077. METHODS Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16). RESULTS Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for Cmax , AUC0-t , and AUC0-inf were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P

Background In phase 2 and 3 studies, fremanezumab, a monoclonal CGRP antibody, was an effective preventive treatment for high-frequency episodic migraine (HFEM) and chronic migraine (CM). Objective Post-hoc analyses evaluated population-wise 50%, 75% and 100% responder rates, and the extent to which individual responders sustained a 50%, 75% and 100% reduction in migraine days, moderate-to-severe (M/S) headache days and days of acute medication use during all three treatment months of the fremanezumab phase 2 studies. Design/methods HFEM patients received either placebo or three once-monthly injections of 225 mg or 675 mg. CM patients received either placebo or three once-monthly injections of 900 mg, or an initial loading dose of 675 mg and subsequent injections of 225 mg. Patients reported headache-related data daily using an electronic diary. Results In the HFEM study, the percent of patients on fremanezumab doses 225 mg and 675 mg were greater compared to the percent of placebo patients with sustained 50% reduction in migraine days (39% and 35% vs. 10% for placebo, both p Conclusions Post-hoc results must be interpreted with caution; nonetheless, a statistically significant percentage of patients who initially responded to fremanezumab within 1 month sustained this response over the subsequent 2 months. Sustained reduction in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments. Trials are registered as http://clinical trials.gov as NCT02025556 and NCT02021773.

Objectives The primary and secondary objectives of this phase 1 study were to evaluate the pharmacokinetic profile, safety, and immunogenicity of fremanezumab subcutaneous (sc) doses tested in phase 2 and 3 trials (225 mg, 675 mg and 900 mg) following single administration in Japanese (n = 32) and Caucasian (n = 32) healthy subjects. Methods Japanese and matched Caucasian healthy subjects were enrolled into one of four cohorts and were randomly assigned to one of four treatments: 225, 675, or 900 mg fremanezumab, or placebo. Pharmacokinetic and immunogenicity sampling, and safety and tolerability assessments occurred at one inpatient visit and 12 ambulatory visits during the 36-week study. Results Pharmacokinetic analyses included those randomized to fremanezumab (n = 24 for each ethnic group) and safety analyses included all subjects enrolled in the study (n = 32 for each ethnic group). Fremanezumab concentration-time profiles and pharmacokinetic parameters per dose were similar for Japanese and Caucasians at all dose levels. Geometric mean ratios (GMRs) for Cmax for Japanese to Caucasian subjects were 0.91, 1.04 and 1.14 for the 225 mg, 675 mg and 900 mg fremanezumab doses. GMRs for AUC0-inf were 0.96, 1.09, and 0.98, respectively. Median Tmax (range 5–11 days) and mean half-lives (range 31–39 days) were similar across doses for both ethnicities. Most frequently occurring adverse events were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis. There was no development of anti-drug-antibodies and no clinically meaningful changes in laboratory findings. Conclusion The results of the pharmacokinetic exposure parameters and safety measures were similar for Japanese and Caucasians and support the once monthly and once quarterly sc injections of fremanezumab.

Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well-established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state-of-the-art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high-resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration-approved generic version of GA, Glatopa (USA-FoGA). While similarities were observed with low-resolution or destructive tests, differences between GA and USA-FoGA were measured with high-resolution methods applied to an intact mixture, including variations in surface charge and a unique, high-molecular-weight, hydrophobic polypeptide population observed only in some USA-FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune-related processes, genome-wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA-FoGA showed that 7-11% of modulated genes were differentially expressed and enriched for immune-related pathways. Thus, differences between USA-FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA.

Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington's disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (β-HTBZ), metabolite profile, safety, and tolerability. In the two-way, cross-over study, the mean elimination half-life of deuterated total (α + β)-HTBZ was doubled compared with nondeuterated total (α + β)-HTBZ, with a twofold increase in overall mean exposure (area under the concentration-time curve from zero to infinity (AUC0-inf )) and a marginal increase in mean peak plasma concentration (Cmax ). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of [14 C]-deutetrabenazine relative to [14 C]-tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active-to-inactive metabolites, attributes considered to provide significant benefits to patients.

Summary Background Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine. Methods In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18–65 years) from 62 sites in the USA who had migraine headaches 8–14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9–12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache-days during weeks 9–12. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at ClinicalTrials.gov, number NCT02025556. Findings Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9–12 was −3·46 days (SD 5·40) in the placebo group, −6·27 days (5·38) in the 225 mg dose group, and −6·09 days (5·22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was −2·81 days (95% CI −4·07 to −1·55; p Interpretation TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials. Funding Teva Pharmaceuticals.

Summary Background Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine. Methods In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group phase 2b study, we enrolled men and women (aged 18–65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9–12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9–12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773. Findings Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9–12 was −59·84 h (SD 80·38) in the 675/225 mg group and −67·51 h (79·37) in the 900 mg group, compared with −37·10 h (79·44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was −22·74 h (95% CI −44·28 to −1·21; p=0·0386), whereas the difference between placebo and 900 mg dose groups was −30·41 h (−51·88 to −8·95; p=0·0057). Adverse events were reported by 36 (40%) patients in the placebo group, 47 (53%) patients in the 675/225 mg dose group, and 41 (47%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17%) patients, 25 (29%) patients, and 28 (32%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1%) patients had serious non-treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment-related adverse events were serious and there were no relevant changes in blood pressure or other vital signs. Interpretation TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial. Funding Teva Pharmaceuticals.

SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077.Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16).Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for CSD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.

Herein we compared 40 mg/mL lots of the active ingredient, glatiramer acetate, manufactured by Mylan/Natco to the active ingredient, glatiramer acetate in Copaxone (Teva Pharmaceuticals, Ltd., Netanya Israel) using physicochemical (PCC) methods and biological assays. No differences were seen between the Mylan/Natco and Teva lots with some low resolution release PCC assays (amino acid analysis, molecular weight distribution, interaction with Coomassie Brilliant Blue G-250). Changes in polydispersity between Mylan/Natco and Copaxone lots were found using size exclusion chromatography and the high resolution PCC method, known as Viscotek, and suggestive of a disparity in the homogeneity of mixture, with a shift towards high molecular weight polypeptides. Using RPLC-2D MALLS, 5 out of 8 Mylan/Natco lots fell outside the Copaxone range, containing a high molecular weight and high hydrophobicity subpopulation of polypeptides not found in Copaxone lots. Cation exchange chromatography showed differences in the surface charge distribution between the Copaxone and Mylan/Natco lots. The Mylan/Natco lots were found to be within Copaxone specifications for the EAE model, monoclonal and polyclonal binding assays and the in vitro cytotoxicity assay, however higher IL-2 secretion was shown for three Mylan/Natco lots in a potency assay. These observations provide data to inform the ongoing scientific discussion about the comparability of glatiramer acetate in Copaxone and follow-on products.

Huntington's disease (HD) is a neurodegenerative condition characterized by pathology in the brain and peripheral tissues. Hyperactivity of the innate immune system, due in part to NFκB pathway dysregulation, is an early and active component of HD. Evidence suggests targeting immune disruption may slow disease progression. Laquinimod is an orally active immunomodulator that down‐regulates proinflammatory cytokine production in peripheral blood mononuclear cells, and in the brain down‐regulates astrocytic and microglial activation by modulating NFκB signalling. Laquinimod had beneficial effects on inflammation, brain atrophy and disease progression in multiple sclerosis (MS) in two phase III clinical trials. This study investigated the effects of laquinimod on hyperactive proinflammatory cytokine release and NFκB signalling in HD patient myeloid cell cultures. Monocytes from manifest (manHD) and pre‐manifest (preHD) HD gene carriers and healthy volunteers (HV) were treated with laquinimod and stimulated with lipopolysaccharide. After 24 h pre‐treatment with 5 μM laquinimod, manHD monocytes released lower levels of IL‐1β, IL‐5, IL‐8, IL‐10, IL‐13 and TNFα in response to stimulation. PreHD monocytes released lower levels of IL‐8, IL‐10 and IL‐13, with no reduction observed in HV monocytes. The effects of laquinimod on dysfunctional NFκB signalling in HD was assessed by inhibitor of kappa B (IκB) degradation kinetics, nuclear translocation of NFκB and interactions between IκB kinase (IKK) and HTT, in HD myeloid cells. No differences were observed between laquinimod‐treated and untreated conditions. These results provide evidence that laquinimod dampens hyper‐reactive cytokine release from manHD and preHD monocytes, with a much reduced effect on HV monocytes. Evidence suggests targeting CNS and peripheral immune disruption may slow Huntington's disease (HD) neurodegenerative processes. The effects of laquinimod, an orally active immunomodulator, on hyperactive cytokine release and dysfunctional NFκB signalling in stimulated myeloid cell cultures from pre‐manifest and manifest HD gene carriers and healthy volunteers were investigated. Laquinimod dampened cytokine release but did not impact NFκB signalling. Read the Editorial Highlight for this article on page 670.

Multiple sclerosis (MS) is a chronic, progressive, disabling disorder characterized by immune-mediated demyelination, inflammation, and neurodegenerative tissue damage in the central nervous system (CNS), associated with frequent exacerbations and remissions of neurologic symptoms and eventual permanent neurologic disability. While there are several MS therapies that are successful in reducing MS relapses, none have been effective in treating all patients. The specific response of an individual patient to any one of the MS therapies remains largely unpredictable, and physicians and patients are forced to use a trial and error approach when deciding on treatment regimens. A priori markers to predict the optimal benefit-to-risk profile of an individual MS patient would greatly facilitate the decision-making process, thereby helping the patient receive the most optimal treatment early on in the disease process. Pharmacogenomic methods evaluate how a person's genetic and genomic makeup affects their response to therapeutics. This review focuses on how pharmacogenomics studies are being used to identify biologically relevant differences in MS treatments and provide characterization of the predictive clinical response patterns. As pharmacogenomics research is dependent on the availability of longitudinal clinical research, studies concerning glatiramer acetate and the interferon beta products which have the majority of published long term data to date are described in detail. These studies have provided considerable insight in the prognostic markers associated with MS disease and potential predictive markers of safety and beneficial response.

Massed training in the conditional discrimination task, the fixed ratio discrimination (FRD) task led to elevated extracellular dopamine (DA) concentrations in the neonatal 6-hydroxydopamine (6-OHDA)-treated rat, a model of Lesch-Nyhan disease (LND). Rats neonatally treated with 6-OHDA or its vehicle were, as adults, implanted with microdialysis probes and assessed for basal pretraining concentrations of DA and its major metabolites. Subsequently, microdialysis samples were collected each day following three separate FRD training periods (trained group) or three separate periods of noncontingent food presentations (untrained group). The present study found that there were significant increases in extracellular DA in the caudate-putamen from basal pretraining concentrations in the repeated sample collections of trained 6-OHDA-lesioned animals but not in the samples of untrained 6-OHDA-lesioned animals. Consistent with previous studies [Brain Res. 508 (1990) 30.], there was an increase in the extracellular concentrations as compared to tissue concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC). Similar to our previous studies with long-term FRD training [Pharmacol. Biochem. Behav. 51 (1995) 861; Brain Res. 713 (1996) 246.], there was also an indication of an increase in cortical and striatal tissue concentration of DA in the trained 6-OHDA-lesioned animals as compared to the untrained 6-OHDA-lesioned animals. The elevations in striatal DA concentrations following operant performance in the present study illustrate how operant procedures of the behavior therapy used with individuals with LND and other mental retardation syndromes may interact with the modulation of dopaminergic function by the pharmaceutical application of DA antagonists to suppress aberrant behaviors.

The effects of footshock sensitization (priming), apomorphine (APO) priming and their combination on behavior and neostriatal and cortical catecholamines were examined in adult rats which had neonatally received bilateral intracerebroventricular injections with 6-hydroxydopamine (6-OHDA; a model of Lesch–Nyhan syndrome (LNS)) or vehicle (unlesioned rats). Lesioned (6-OHDA-treated) rats displayed self-biting (SB; 7/20 rats) and self-injurious behavior (SIB; 1/20 rats) during APO priming, but not during footshock priming. During subsequent acute cumulative APO dosing, 20–30% of lesioned rats primed with APO alone or footshock alone displayed SB and SIB. However, SB and SIB incidence in APO+footshock-primed lesioned rats was nearly tripled. Dopamine (DA) synthesis, metabolism and extracellular concentrations (disposition) in unlesioned rats and in cortices of lesioned animals were unaffected by priming. In lesioned rats primed with APO alone or footshock alone, only neostriatal 3-methoxytyramine (3-MT) was significantly increased. However, neostriatal DA and metabolite concentrations (and norepinephrine (NE)) were all significantly elevated in lesioned rats primed with both APO and footshock. These results confirm that neonatal 6-OHDA-induced neostriatal catecholamine depletion can be antagonized by experiential change, suggest that behavioral and neurochemical cross-sensitization between APO and footshock in such rats is unidirectional and support the view that stress can exacerbate the incidence of SIB in LNS.

Rats received either vehicle (controls) or 100 μg of 6-hydroxydopamine (6HD) base intracisternally on postnatal day 5. At 3 mo of age, striatal and cortical catecholamine and metabolite levels were determined in some animals. Others were subjected to 4.5 mo of training on incrementally more difficult fixed-ratio (FR) discriminations; 2 mo later, their levels were determined. Learning was essentially unaffected by 6HD even though errors in all animals increased with increases in discrimination difficulty and 6HD had markedly depleted levels in the 3-mo-old animals. Moreover, an initial response-rate deficit in 6HD-treated rats disappeared with training. However, after training, levels in 6HD-treated rats were not only not depleted, they were as much as 661% of those in controls. These and others of our findings indicate that FR discrimination training can induce persistent increases in brain catecholamine utilization. They also appear to be the first to suggest that at least some neurochemical effects of neonatal 6HD are not necessarily irreversible, and that such a reversal can be experientially induced and possibly functionally beneficial.

Fixed-ratio (FR) discrimination learning in adult male spontaneously hypertensive rats (SHR), methylazoxymethanol-induced microencephalic Sprague-Dawley (MAM), and Sprague-Dawley control rats was examined. SHR and MAM rats had little problem learning incrementally more difficult FR discriminations (FR1 vs. FR16, FR4 vs. FR16, and FR8 vs. FR16) that resulted in parallel increases in errors in all animals, and displayed only modest learning deficits during a subsequent FR4 vs. FR16 position reversal. When training involved nonincremental changes in difficulty (FR8 vs. FR16, FR4 vs. FR16, FR8 vs. FR16, FR12 vs. FR16, and FR14 vs. FR16), SHR and MAM rats evidenced relatively large learning deficits during the initial FR8 vs. FR16 discrimination but had no difficulty with the last two discriminations. Furthermore, training selectively and significantly elevated hippocampal weight in MAM rats. These findings: a) question prior suggestions that MAM and SHR model separate human developmental disabilities; b) indicate that manifestation of learning deficits in even markedly brain-damaged organisms depends on initial task difficulty and can be overcome by experience; and c) are the first indicating that training-induced antagonism of prenatally induced hippocampal hypoplasia and its consequences is possible.

This paper reviews the research on three animal models related to self-injurious behavior (SIB), stereotypy, and aggression and their susceptibility to stress. These studies support the importance of stress and differences in organic dysfunction in the etiology, maintenance, and topography of SIB and their relationship to stereotypy and aggression. Several organic risk factors associated with mental retardation also increase the susceptibility to manifestation of SIB and related behaviors. © 1995 Wiley-Liss, Inc.

The purpose of this review is to organize the literature over the past 50 years on animal models for self‐injurious behavior (SIB). Of the many animal models for SIB, there are four models for inducing it which have been very productive: (1) the isolate‐rearing model in rhesus monkeys; (2) the neonate 6‐hydroxydopamine (6‐OHDA) lesion model in rats; (3) the administration of stimulants, e.g. amphetamine and pemoline to normal rats; and (4) the administration of the l‐type calcium channel blocker BayK8644 to mice. A model of prevention of repetitive behavior in deer mice, some of which is self‐injurious, is based upon environmental enrichment and environmental complexity. The final section of the paper reviews a 10‐year research program by the authors on training‐induced recovery from SIB. In general, the animal literature supports the neurobiological bases for induction, prevention, and recovery from SIB.

Fixed-ratio discrimination (FRD) training session-accuracy curves were constructed using first-order, nonlinear regression and probit analyses to determine maximal (asymptotic) accuracy and the number of sessions required to reach half-maximal accuracy. Increased FRD difficulty (reductions in the differences between the 2 fixed-ratio values to be discriminated) and a training parameter change each increased the number of sessions required to reach half-maximal accuracy and decreased maximal FRD accuracy (i.e., session-accuracy curves were shifted down and to the right) regardless of analysis procedure. These findings indicate that the above manipulations induced mixed competitive-noncompetitive inhibition of the rate of FRD learning. Microencephalic rats were more sensitive to increases in FRD difficulty, whereas control rats were more sensitive to the training parameter change.

Many individuals with mental retardation exhibit chronic aberrant behaviors (CABs) that includes hyperactive, stereotyped, aggressive, and self-injurious behaviors. Brain imaging studies have found that several of these individuals have abnormalities in their dopaminergic neurotransmitter systems that are thought to be responsible in part, for the development of these behaviors. The present study evaluated the effects of a selective dopamine re-uptake blocker, GBR-12909 in three animal models of varying striatal dopamine concentrations. The three animal models included the neonatal 6-hydroxydopamine (6-OHDA)-lesioned rat, a model of dopamine neuronal depletion, the prenatal methylazoxymethanol (MAM)-exposed rat, a model of hyper-dopaminergic innervation and control rats, a model of normal dopaminergic function. The animals were given five daily injections of GBR-12909 and videotaped observations were conducted immediately following the injections and 6 h later. The results of the study indicate that the MAM-treated rats exhibited more hyperactive behaviors than either the 6-OHDA or the control animals in response to the GBR-12909 injections. However, the 6-OHDA and control rats exhibited more self-injurious behaviors than the MAM rats. Interestingly, the topography of the self-injurious behavior exhibited differed from that we have previously observed in 6-OHDA lesioned rats following dopamine agonists and resembles the mouthing behaviors seen in some individuals with mental retardation, in particular those with Rett syndrome. These findings indicate the models of varying dopaminergic function interact differently with a dopamine re-uptake blocker than dopamine agonists and that the partially dopamine depleted model may model the behaviors seen in individuals with Rett syndrome.