Interdisciplinary rehabilitation for persisting post-concussion symptoms after mTBI: N=15 single case experimental design.

BACKGROUND: Despite clinical guidelines recommending an interdisciplinary approach to persisting post-concussion symptom (PPCS) management, evaluations of interdisciplinary interventions remain scant. OBJECTIVES: This pilot study aimed to explore the feasibility and preliminary efficacy of an interdisciplinary intervention for PPCSs. METHOD: A single-case experimental design with randomisation to multiple baselines (2, 4, or 6 weeks) was repeated across 15 participants (53% female) with mild traumatic brain injury (mean age 38.3 years, SD 15.7). The 12-week treatment incorporated psychology, physiotherapy, and medical interventions. Feasibility outcomes included recruitment and retention rates, adverse events, treatment adherence and fidelity. Patient-centred secondary outcomes included the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), assessed 3 times per week during the baseline and treatment phases, and at the 1- and 3-month follow-ups. Other secondary outcomes included measures of mood, sleep and fatigue, physical functioning, health-related quality of life, illness perceptions, and goal attainment. Changes in PPCSs were evaluated using systematic visual analysis and Tau-U. Clinically significant changes in secondary outcomes were explored descriptively. RESULTS: 16/26 individuals assessed for eligibility were enroled (61% recruitment rate); 15 completed the post-treatment follow-ups, and 13 completed the 1- and 3-month follow-up assessments (81% retention rate). High treatment adherence and competence in delivering treatments was observed. Moderate-large effect sizes for reducing PPCSs were observed in 12/15 cases, with 7/15 reaching statistical significance. Improvements were maintained at the 1- and 3-month follow-ups and were accompanied by reductions in fatigue, sleep difficulties, and mood symptoms, and changes in illness perceptions. All participants had clinically significant improvements in at least 1 outcome, with 81% of individual therapy goals achieved. CONCLUSIONS: This pilot study provided preliminary support for a subsequent randomised controlled trial (RCT), with satisfactory recruitment, retention, treatment compliance, and treatment fidelity. Improvement was evident on participant outcomes including symptom reduction and goal attainment, suggesting that progressing to a phase-II RCT is worthwhile. Findings highlight the potential benefit of individualized interdisciplinary treatments.

Moving forward on the road to recovery after concussion: participant experiences of interdisciplinary intervention for persisting post-concussion symptoms.

PURPOSE: Many factors contribute to persisting post-concussion symptoms (PPCSs), necessitating multi-modal treatment. Quantitative investigations have shown the potential of interdisciplinary intervention to reduce the burden of PPCSs and facilitate return to activities. There are often varied responses to intervention, warranting further investigation of potential factors underlying treatment response. This study aimed to explore participant experiences of i-RECOveR, an interdisciplinary intervention for PPCSs and its impact on symptoms, daily function, and concussion beliefs. MATERIALS AND METHOD: Semi-structured interviews were conducted 1-month post-treatment via videoconferencing with 13 individuals (61% female) with mild traumatic brain injury (Mage=39.77 years, SD = 16.27) who participated in i-RECOveR. Interview transcripts were analysed thematically. RESULTS: Three themes reflected participants' treatment journeys from concussion to life after treatment: (1) Dissatisfaction with Previous Consultations, reflected personal experiences prior to commencing treatment; (2) Perceived Active Ingredients of Intervention, reflected participant experiences of i-RECOveR; and (3) Impact of Interdisciplinary Intervention, reflected a range of positive changes after completing i-RECOveR. CONCLUSIONS: Findings highlight current gaps in the acute management of concussion and provide end-user insights into the facilitators and barriers of treatment engagement and response. Responses also highlight the potential positive impact of interdisciplinary treatments. Clinician perspectives should be explored in future research.

Access to additional training in concussion care and referral pathways may help medical practitioners manage patients after concussion.Clinicians working with individuals with persisting post-concussion symptoms should develop an understanding of the individual's perceived control over their symptoms, and work with them toward increasing autonomy and control and recognition that symptoms are often multifactorial in nature.Persisting post-concussion symptom rehabilitation may be improved by taking an interdisciplinary approach that is integrated individualised, and is specialised for concussion.Telehealth and hybrid treatment models are well tolerated by individuals with persisting post-concussion symptoms and may facilitate treatment engagement, especially for individuals with mild traumatic brain injury who report disabling symptoms made worse by travelling to in-person treatments.

TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1.

Mitophagy is a form of selective autophagy that disposes of superfluous and potentially damage-inducing organelles in a tightly controlled manner. While the machinery involved in mitophagy induction is well known, the regulation of the components is less clear. Here, we demonstrate that TNIP1 knockout in HeLa cells accelerates mitophagy rates and that ectopic TNIP1 negatively regulates the rate of mitophagy. These functions of TNIP1 depend on an evolutionarily conserved LIR motif as well as an AHD3 domain, which are required for binding to the LC3/GABARAP family of proteins and the autophagy receptor TAX1BP1, respectively. We further show that phosphorylation appears to regulate its association with the ULK1 complex member FIP200, allowing TNIP1 to compete with autophagy receptors, which provides a molecular rationale for its inhibitory function during mitophagy. Taken together, our findings describe TNIP1 as a negative regulator of mitophagy that acts at the early steps of autophagosome biogenesis.

Interdisciplinary Rehabilitation for Concussion Recovery (i-RECOveR): protocol of an investigator-blinded, randomised, case series with multiple baseline design to evaluate the feasibility and preliminary efficacy of a 12-week treatment for persistent post-concussion symptoms.

BACKGROUND: Up to 25% of concussed individuals experience persistent post-concussion symptoms (PPCSs) which may interfere with the return to pre-injury activities and cause significant stress. Given that multiple etiological factors are thought to contribute to PPCSs, an interdisciplinary approach is recommended. This pilot study aims to primarily investigate the feasibility of a novel interdisciplinary treatment for PPCSs. Given this intervention is novel, uncertainty exists in terms of potential recruitment and retention rates, adverse events, and treatment adherence and fidelity. These factors will be explored to inform the feasibility of a phase-2 randomised controlled trial. Preliminary efficacy of this intervention will also be explored. METHODS: Fifteen individuals with mild traumatic brain injury and PPCSs will receive up to 12 weeks of interdisciplinary treatments including psychology, physiotherapy, and medical interventions. Primary feasibility outcomes including data on recruitment and retention rates and treatment adherence will be explored descriptively. The cognitive therapy rating scale will be used to assess treatment fidelity. A single-case series with multiple baseline design will be used to explore preliminary efficacy. Participants will be randomly assigned to baseline phases of 2, 4, or 6 weeks. Regarding patient-centred secondary outcomes, the Rivermead Post-Concussion Symptoms Questionnaire will be assessed three times a week during baseline and treatment phases. Secondary outcomes also include measures of mood, sleep and fatigue, physical functioning, return to activity, and health-related quality of life. Patient-centred outcomes will be assessed at baseline, pretreatment, post-treatment, and one- and three-month follow-up. Thematic analysis of participant experiences will be explored through qualitative interviews. DISCUSSION: Results from this trial will inform the feasibility and preliminary efficacy of this interdisciplinary concussion intervention and whether proceeding to a future definitive phase-2 randomised controlled trial is worthwhile. Understanding the end-user perspective of the treatment will also enable modifications to the treatment protocol for future trials to best suit the needs of individuals with PPCSs after mTBI. Outcomes from this trial can be directly translated into community rehabilitation programmes. TRIAL REGISTRATION: ANZCTR, ACTRN12620001111965. Registered 27 October 2020, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379118.

Visible Signs of Concussion and Cognitive Screening in Community Sports.

Video surveillance and detection of players with visible signs of concussion by experienced medical staff facilitates rapid on-field screening of suspected concussion in professional sports. This method, however has not been validated in community sports where video footage is unavailable. This study aimed to explore the utility of visible signs of concussion to identify players with decrements in performance on concussion screening measures. In this observational prospective cohort study, personnel with basic training observed live matches across a season (60 matches) of community male and female Australian football for signs of concussion outlined in the community-based Head Injury Assessment form (HIAf). Players identified to have positive signs of concussion (CoSign+) following an impact were compared with players without signs (CoSign-). Outcome measures, the Sport Concussion Assessment Tool (SCAT3) and Cogstate, were administered at baseline and post-match. CoSign+ (n = 22) and CoSign- (n = 61) groups were similar with respect to age, sex, education, baseline mood, and medical history. CoSign+ players exhibited worse orientation, concentration, and recall, and slower reaction time in attention and working memory tasks. Comparing individual change from baseline to post-match assessment revealed 100% (95% confidence interval [CI]: 84-100%) of CoSign+ players demonstrated clinically significant deficits on SCAT3 or Cogstate tasks, compared with 59% (95% CI: 46-71%) of CoSign- players. All CoSign+ players observed to have a blank/vacant look demonstrated clinically significant decline on the Standardized Assessment of Concussion (SAC). Detection of visible signs of concussion represents a rapid, real-time method for screening players suspected of concussion in community sports where video technology and medical personnel are rarely present. Consistent with community guidelines, it is recommended that all CoSign+ players be immediately removed from play for further concussion screening.

Re-Analysis of the STEADY-PD II Trial-Evidence for Slowing the Progression of Parkinson's Disease.

BACKGROUND: Recent examination of the STEADY-PD III isradipine clinical trial data concluded that early-stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. OBJECTIVES: To test this hypothesis, the data from the STEADY-PD II isradipine clinical trial, in which an extended-release (ER) formulation of the drug was used, was re-examined. METHODS: The re-analysis of the STEADY-PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. RESULTS: Participant cohorts were well-matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. CONCLUSIONS: These results are consistent with the recent secondary analysis of the STEADY-PD III clinical trial-suggesting that clinically attainable brain exposure to isradipine may slow early-stage PD progression. © 2021 International Parkinson and Movement Disorder Society.

A pilot case crossover study of the use of padded headgear in junior Australian football.

Aim: To explore soft-shell padded headgear (HG) use, player behavior and injuries associated with HG in junior Australian football. Methods: Prospective case-crossover with head impact measurement, injury surveillance and video review. Results: 40 players (mean age: 12.43 years, standard deviation: 1.36) across 15 matches were observed. Frequency of head/neck (p = 0.916) or body (p = 0.883) contact events, and match incidents were similar between HG and no HG conditions. Without HG, females had higher frequency of body contacts compared with males (p = 0.015). Males sustained more body contacts with HG than without HG (p = 0.013). Conclusion: Use of HG in junior football was not associated with injury or head contact rate. Associations between HG use and body contact may differ across sexes. (ID: ACTRN12619001165178).

Soft-shell headgear, concussion and injury prevention in youth team collision sports: a systematic review.

OBJECTIVES: To assess the association between soft-shell headgear (HG) use and sports-related concussion (SRC). Secondary objectives were to assess the association between HG and superficial head injury and investigate potential increase in injury risk among HG users. DESIGN: A systematic search in Ovid MEDLINE, Cochrane Library, Scopus, PsycINFO and SPORTDiscus was conducted in April 2020. Inclusion criteria were youth <18, English language, in vivo studies published after 1980 that evaluated SRC and other injury incidence in HG users compared with non-users. OUTCOME MEASURES: Incidence rates of SRC, superficial head injury or other injuries. RESULTS: Eight studies were eligible. The majority (n=5) reported no difference in the rate of SRC among HG users versus non-users. One rugby study identified significantly lower risk of SRC for non-HG users (risk ratio (RR) 0.63; 95% CI 0.41 to 0.98) compared with HG users, whereas a cross-sectional survey of soccer players indicated higher risk of SRC for non-HG users (RR 2.65; 95% CI 1.23 to 3.12) compared with HG users. Three of the four studies investigating superficial head injury found no significant differences with HG use, though the soccer survey reported reduced risk among HG users (RR 1.86; 95% CI 0.09 to 0.11). Increased incidence of injuries to all body regions for rugby HG users was reported in two studies with adjusted RRs of 1.16 (95% CI 1.04 to 1.29) and 1.23 (95% CI 1.00 to 1.50). CONCLUSIONS: HG use was not associated with reduced rates of SRC or superficial head injury in youth soccer and rugby. The possibility of increased injury risk to all body regions for rugby HG users was raised. The need for research specific to youth and female athletes was highlighted. PROSPERO REGISTRATION NUMBER: CRD42018115310.

Secondary osteon structural heterogeneity between the cranial and caudal cortices of the proximal humerus in white-tailed deer.

Cortical bone remodeling is an ongoing process triggered by microdamage, where osteoclasts resorb existing bone and osteoblasts deposit new bone in the form of secondary osteons (Haversian systems). Previous studies revealed regional variance in Haversian systems structure and possibly material, between opposite cortices of the same bone. As bone mechanical properties depend on tissue structure and material, it is predicted that bone mechanical properties will vary in accordance with structural and material regional heterogeneity. To test this hypothesis, we analysed the structure, mineral content and compressive stiffness of secondary bone from the cranial and caudal cortices of the white-tailed deer proximal humerus. We found significantly larger Haversian systems and canals in the cranial cortex but no significant difference in mineral content between the two cortices. Accordingly, we found no difference in compressive stiffness between the two cortices and thus our working hypothesis was rejected. As the deer humerus is curved and thus likely subjected to bending during habitual locomotion, we expect that similar to other curved long bones, the cranial cortex of the deer humerus is likely subjected primarily to tensile strains and the caudal cortex is subject primarily to compressive strains. Consequently, our results suggest that strain magnitude (larger in compression) and sign (compression versus tension) affect the osteoclasts and osteoblasts differently in the basic multicellular unit. Our results further suggest that osteoclasts are inhibited in regions of high compressive strains (creating smaller Haversian systems) while the osteoid deposition and mineralization by osteoblasts is not affected by strain magnitude and sign.

The potential of head acceleration measurement to augment current best practice in concussion screening in professional Australian football players.

OBJECTIVE: To explore the potential utility of head acceleration event (HAE) measurements to augment identification of players for further concussion screening in non-helmeted contact sport. DESIGN: Prospective observational pilot study. PARTICIPANTS: 210 (118 female) professional Australian football players in 2017 season. METHODS: Players wore the X-Patch® accelerometer for one match each with data collected across 14 matches. Players with HAEs above thresholds associated with concussion, 95 g (males) or 85.5 g (females), were compared to players identified to have suspected concussion by club personnel during the inspected matches. Video review of matches was undertaken by a physician blinded to HAEs to identify players with concussive signs. RESULTS: Among 26 players (50% female) with HAEs above threshold, two players were screened for concussion. Of the remaining 24 players, nine were not visible on video at the HAE time, six sustained verifiable head impacts, and nine sustained verifiable body impacts with no head impacts. Among 184 players with HAEs below threshold, five players were screened. CONCLUSION: Players were identified to have head impacts and suspected concussion in the absence of HAEs above threshold. Use of X-Patch® was not sufficiently reliable for identifying players for further concussion screening in professional Australian football. Video review of head impacts remains essential in concussion screening.

An Investigation of Factors Associated With Head Impact Exposure in Professional Male and Female Australian Football Players.

BACKGROUND: Exposure to head acceleration events (HAEs) has been associated with player sex, player position, and player experience in North American football, ice hockey, and lacrosse. Little is known of these factors in professional Australian football. Video analysis allows HAE verification and characterization of important determinants of injury. PURPOSE: To characterize verified HAEs in the nonhelmeted contact sport of professional Australian football and investigate the association of sex, player position, and player experience with HAE frequency and magnitude. STUDY DESIGN: Descriptive epidemiology study. METHODS: Professional Australian football players wore a nonhelmeted accelerometer for 1 match, with data collected across 14 matches. HAEs with peak linear accelerations (PLAs) ≥30g were verified with match video. Verified HAEs were summarized by frequency and median PLA and compared between the sexes, player position, and player experience. Characterization of match-related situations of verified HAEs was conducted, and the head impact rate per skill execution was calculated. RESULTS: 92 male and 118 female players were recruited during the 2017 season. Male players sustained more HAEs (median, 1; IQR, 0-2) than female players (median, 0; IQR, 0-1; P = .007) during a match. The maximum PLAs incurred during a match were significantly higher in male players (median, 61.8g; IQR, 40.5-87.1) compared with female players (median, 44.5g; IQR, 33.6-74.8; P = .032). Neither player position nor experience was associated with HAE frequency. Of all verified HAEs, 52% (n = 110) occurred when neither team had possession of the football, and 46% (n = 98) were caused by contact from another player attempting to gain possession of the football. A subset of HAEs (n = 12; 5.7%) resulted in players seeking medical aid and/or being removed from the match (median PLA, 58.8g; IQR, 34.0-89.0), with 2 (male) players diagnosed with concussion after direct head impacts and associated PLAs of 62g and 75g, respectively. In the setting of catching (marking) the football, female players exhibited twice the head impact rate (16 per 100 marking contests) than male players (8 per 100 marking contests). CONCLUSION: Playing situations in which players have limited control of the football are a common cause of impacts. Male players sustained a greater exposure to HAEs compared with female players. Female players, however, sustained higher exposure to HAEs than male players during certain skill executions, possibly reflecting differences in skill development. These findings can therefore inform match and skill development in the emerging professional women's competition of Australian football.

Are we crying Wolff? 3D printed replicas of trabecular bone structure demonstrate higher stiffness and strength during off-axis loading.

Roux's principle of bone functional adaptation postulates that bone tissue, and particularly trabecular bone tissue, responds to mechanical stimuli by adjusting (modeling) its architecture accordingly. Hence, it predicts that the new modeled trabecular structure is mechanically improved (stiffer and stronger) in line with the habitual in vivo loading direction. While previous studies found indirect evidence to support this theory, direct support was so far unattainable. This is attributed to the fact that each trabecular bone is unique, and that trabecular bone tissue tends to be damaged during mechanical testing. Consequently, a unique modeled trabecular structure can be mechanically tested only along one direction and a comparison to other directions for that specific structure is impossible. To address this issue, we have 3D printed 10 replicas of a trabecular structure from a sheep talus cropped along the 3 principal axes of the bone and in line with the principal direction of loading (denoted on-axis model). Next, we have rotated the same cropped trabecular structure in increments of 10° up to 90° to the bone principal direction of loading (denoted off-axis models) and printed 10 replicas of each off-axis model. Finally, all on-axis and off-axis 3D printed replicas were loaded in compression until failure and trabecular structure stiffness and strength were calculated. Contrary to our prediction, and conflicting with Roux's principle of bone functional adaptation, we found that a trabecular structure loaded off-axis tended to have higher stiffness and strength values when compared to the same trabecular structure loaded on-axis. These unexpected results may not disprove Roux's principle of bone functional adaptation, but they do imply that trabecular bone adaptation may serve additional purposes than simply optimizing bone structure to one principal loading scenario and this suggests that we still don't fully understand bone modeling in its entirety.

Frequency and Magnitude of Game-Related Head Impacts in Male Contact Sports Athletes: A Systematic Review and Meta-Analysis.

BACKGROUND: Sensor devices have enabled estimations of head impact kinematics across contact sports. OBJECTIVES: To quantitatively report the magnitude (linear and rotational acceleration) and frequency of game-related head impacts recorded in male contact sports athletes. METHODS: A systematic review was conducted in June 2017. Inclusion criteria were English-language in vivo studies published after 1990 with a study population of male athletes aged ≥ 16 years, in any sport, where athletes were instrumented with an accelerometer device for measuring head impacts. Study populations were not limited to players with a clinical diagnosis of concussion. RESULTS: Twenty-one studies met the inclusion criteria with 12 conducted on American Football athletes. Six of these studies were included for meta-analysis. At a threshold of 10g, amateur rugby players sustained the most impacts per player per game (mean = 77, SD = 42), followed by amateur Australian Football (mean = 29, SD = 37) and collegiate lacrosse athletes (mean = 11.5, SD = 3.6). At thresholds of greater than 14.4g, high school American Football athletes sustained between 19 (SD = 19.1) and 24.4 (SD = 22.4) impacts per player per game. Statistically significant heterogeneity was observed among the included studies, and meta-analysis of impact magnitude was limited. CONCLUSIONS: The frequency of "head acceleration events" was quantified and demonstrated substantial variation in methodology and reporting of results. Future research with standardised reporting of head impacts and inclusion of non-helmeted sports is warranted to enable more robust comparisons across sports. PROSPERO ID: CRD42017070065.

Prevalence of Dyskinesia and OFF by 30-Minute Intervals Through the Day and Assessment of Daily Episodes of Dyskinesia and OFF: Novel Analyses of Diary Data from Gocovri Pivotal Trials.

BACKGROUND: Parkinson's disease (PD) patients using levodopa commonly develop dyskinesia and OFF episodes that reduce quality of life. OBJECTIVE: Evaluate prevalence of troublesome dyskinesia and OFF through the day, assessed by 30-minute intervals, as well as the mean number and duration of troublesome dyskinesia and OFF episodes, transitions between PD states, and effects of Gocovri® (amantadine) extended release capsules on these episodes. METHODS: Evaluate diary data from pooled Gocovri phase 3, placebo-controlled trials-analyzed for 17 hours following wake-up-at baseline and week 12. RESULTS: Diaries were evaluable for 162 patients. At baseline, 67% of patients woke up OFF, with prevalence decreasing to 13% at 2 hours and then remaining relatively steady at ∼12% (range, 6-17%) across half-hour intervals thereafter. Troublesome dyskinesia prevalence rose steadily from 5% to 24% over the first 2 hours, then fluctuated between 20% and 44% through the rest of the waking day. At baseline, patients experienced a mean of 3.0 daily episodes of troublesome dyskinesia (average duration 2.0 hours each), and 2.2 daily episodes of OFF (average duration 1.1 hour each). At week 12, Gocovri-treated patients showed greater reductions than placebo in troublesome dyskinesia and OFF episodes per day (treatment difference: -1.0 episodes and -0.4 episodes, respectively) and average episode duration (treatment difference: -0.6 hours and -0.3 hours, respectively). Mean duration of individual episodes of ON without troublesome dyskinesia (Good ON) increased by 5.0 hours for Gocovri, compared with 2.0 hours for placebo. Patients taking Gocovri experienced 2.2 fewer transitions between states than patients taking placebo. CONCLUSIONS: Troublesome dyskinesia and OFF occurred in the morning and throughout the waking day. Gocovri-treated patients experienced fewer, shorter episodes of both troublesome dyskinesia and OFF, thereby increasing the duration of continuous Good ON episodes and reducing the frequency of transitions between motor states.

Pharmacokinetics of ADS-5102 (Amantadine) Extended Release Capsules Administered Once Daily at Bedtime for the Treatment of Dyskinesia.

BACKGROUND: Preclinical and clinical studies suggest amantadine immediate-release (IR) may reduce dyskinesia in Parkinson's disease (PD), although higher doses are associated with increased CNS adverse events (AEs). ADS-5102 is an extended release amantadine capsule formulation, designed for once-daily dosing at bedtime (qhs) to provide high concentrations upon waking and throughout the day, with lower concentrations in the evening. The pharmacokinetics (PK) of ADS-5102 were assessed in two phase I studies in healthy subjects, and a blinded, randomized phase II/III dose-finding study in PD patients. METHODS: The first phase I study assessed single ADS-5102 doses (68.5, 137, and 274 mg) in a crossover design, whereas the second phase I study evaluated ADS-5102 137 mg for 7 days followed by amantadine IR 81 mg twice daily (or reverse order). In the phase II/III double-blind study, PD patients with dyskinesia were randomized to ADS-5102 (210, 274, or 338 mg) or placebo for 8 weeks. RESULTS: Single ADS-5102 doses resulted in a slow initial rise in amantadine plasma concentration, with delayed time to maximum concentration (12-16 h). Amantadine plasma concentrations were higher in PD patients versus healthy volunteers. The steady-state profile of once-daily ADS-5102 was significantly different from that of twice-daily amantadine IR, such that the two formulations are not bioequivalent. PK modeling suggested the recommended daily ADS-5102 dosage (274 mg qhs) resulted in 1.4- to 2.0-fold higher amantadine plasma concentrations during the day versus amantadine IR. CONCLUSIONS: ADS-5102 can be administered once-daily qhs to achieve high amantadine plasma concentrations in the morning and throughout the day, when symptoms of dyskinesia occur.

Pharmacokinetic/Pharmacodynamic Correlation Analysis of Amantadine for Levodopa-Induced Dyskinesia.

Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (∼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.

Amantadine improves cognitive outcome and increases neuronal survival after fluid percussion traumatic brain injury in rats.

This study evaluated the effects of clinically relevant concentrations of amantadine (AMT) on cognitive outcome and hippocampal cell survival in adult rats after lateral fluid percussion traumatic brain injury (TBI). AMT is an antagonist of the N-methyl-D-aspartate-type glutamate receptor, increases dopamine release, blocks dopamine reuptake, and has an inhibitory effect on microglial activation and neuroinflammation. Currently, AMT is clinically used as an antiparkinsonian drug. Amantadine or saline control was administered intraperitoneally, starting at 1 h after TBI followed by dosing three times daily for 16 consecutive days at 15, 45, and 135 mg/kg/day. Terminal blood draws were obtained from TBI rats at the time of euthanasia at varying time points after the last amantadine dose. Pharmacokinetics analysis confirmed that the doses of AMT achieved serum concentrations similar to those observed in humans receiving therapeutic doses (100-400 mg/day). Acquisition of spatial learning and memory retention was assessed using the Morris water maze (MWM) on days 12-16 after TBI. Brain tissues were collected and stained with Cresyl-violet for long-term cell survival analysis. Treatment with 135mg/kg/day of AMT improved acquisition of learning and terminal cognitive performance on MWM. The 135-mg/kg/day dosing of AMT increased the numbers of surviving CA2-CA3 pyramidal neurons at day 16 post-TBI. Overall, the data showed that clinically relevant dosing schedules of AMT affords neuroprotection and significantly improves cognitive outcome after experimental TBI, suggesting that it has the potential to be developed as a novel treatment of human TBI.

Combination therapy with amantadine, oseltamivir and ribavirin for influenza A infection: safety and pharmacokinetics.

BACKGROUND: Antiviral resistance among influenza A viruses is associated with high morbidity and mortality in immunocompromised hosts. However, treatment strategies for drug-resistant influenza A are not established. A triple-combination antiviral drug (TCAD) regimen consisting of amantadine (AMT), oseltamivir (OSL) and ribavirin (RBV) demonstrated good efficacy in an animal model. METHODS: We first analysed the pharmacokinetics (PKs) of TCAD therapy in healthy volunteers. We then performed a pilot study of TCAD therapy in patients undergoing chemotherapy or haematopoietic cell transplantation. AMT (75 mg), OSL (50 mg) and RBV (200 mg) were administered three times a day for 10 days. The safety and PKs of TCAD therapy were monitored. RESULTS: The PKs of TCAD therapy in healthy volunteers was shown to be similar to the PKs of each drug individually from a single dose. In the pilot study, six immunocompromised patients received TCAD therapy and one patient received OSL monotherapy. All but one patient completed 10 days of TCAD therapy without side effects; one patient receiving TCAD was withdrawn from the study because of respiratory failure and ultimately recovered. Viral load was decreased after TCAD therapy, despite the presence of either AMT- or OSL-resistant virus in two cases. One patient with 2009 influenza A/H1N1 receiving OSL monotherapy developed confirmed OSL resistance during treatment. CONCLUSIONS: TCAD therapy had similar PKs to each individual antiviral during monotherapy following a single dose and can be administered safely in immunocompromised patients.

Treatment of oseltamivir-resistant influenza A (H1N1) virus infections in mice with antiviral agents.

Influenza A/Mississippi/03/2001 (H1N1) and A/Hong Kong/2369/2009 (H1N1) viruses containing the neuraminidase gene mutation H275Y (conferring resistance to oseltamivir) were adapted to mice and evaluated for suitability as models for lethal infection and antiviral treatment. The viral neuraminidases were resistant to peramivir and oseltamivir carboxylate but sensitive to zanamivir. Similar pattern of antiviral activity were seen in MDCK cell assays. Lethal infections were achieved in mice with the two viruses. Oral oseltamivir at 100 and 300mg/kg/day bid for 5day starting at -2h gave 30% and 60% protection from death, respectively, due to the A/Mississippi/03/2001 infection. Intraperitoneal treatments with zanamivir at 30 and 100mg/kg/day starting at -2h gave 60% and 90% protection, respectively. Neither compound at <300mg/kg/day protected mice when treatments began at +24h. Amantadine was effective at 10, 30, and 100mg/kg/day, rimantadine was protective at 10 and 30mg/kg/day (highest dose tested), and ribavirin was active at 30 and 75mg/kg/day, with survival ranging from 60-100% for oral treatments initiated at -2h. For treatments begun at +24h, amantadine was protective at 30 and 100mg/kg/day, rimantadine showed efficacy at 10 and 30mg/kg/day, and ribavirin was active at 75mg/kg/day, with 60-100% survival per group. In the A/Hong Kong/2369/2009 infection, oral oseltamivir at 100 and 300mg/kg/day starting at -2h gave 50% and 70% protection from death, respectively. These infection models will be useful to study newly discovered anti-influenza virus agents and to evaluate compounds in combination.