Cognitive and autonomic dysfunction in presymptomatic and early Huntington’s disease

Huntington’s disease is characterized by disorders of movement, cognition and behavior. Individuals with Huntington’s disease display aberrant changes in the autonomic nervous system that are detected even before the onset of other symptoms. Subtle cognitive dysfunction may start before other clinical manifestations. The aim of the present study was to investigate the autonomic nervous system response to mental arithmetic and the relationship between the autonomic and cognitive/motor function in presymptomatic and early Huntington’s disease. We examined 15 presymptomatic Huntington’s disease gene carriers (PHD), 15 early Huntington’s disease patients (EHD) and 30 healthy controls. PHD and EHD groups were determined according to Unified Huntington’s Disease Rating Scale (UHDRS) motor score. ECG, heart rate, systolic and diastolic blood pressure, and cutaneous laser Doppler flux were measured during rest and during a simple mental arithmetic test. UHDRS cognitive test battery was applied to determine cognitive dysfunction. During mental arithmetic, the heart rate of PHD/EHD increased significantly less than that of controls. Decreased microvascular response to mental arithmetic was found in EHD. Significant correlations for the PHD/EHD group were found between laser Doppler flux response and Symbol Digit Modalities Test score, and between laser Doppler flux response and UHDRS motor score. It seems that central autonomic dysregulation of cardiovascular system in Huntington’s disease goes along with the degeneration of other central neuronal systems. This finding is relevant as it could enable simple and noninvasive testing of disease progression.     

Adverse Effects of Synthetic Cannabinoids: Management of Acute Toxicity and Withdrawal

Although several chemical structural classes of synthetic cannabinoids (SCs) were recently classified as Schedule I substances, rates of use and cases of serious toxic effects remain high. While case reports and media bring attention to severe SC toxicity, daily SC use resulting in dependence and withdrawal is a significant concern that is often overlooked when discussing the risks of these drugs. There is a rich literature on evidence-based approaches to treating substance use disorders associated with most abused drugs, yet little has been published regarding how to best treat symptoms related to SC dependence given its recency as an emerging clinically significant issue. This review provides a background of the pharmacology of SCs, recent findings of adverse effects associated with both acute intoxication and withdrawal as a consequence of daily use, and treatment approaches that have been implemented to address these issues, with an emphasis on pharmacotherapies for managing detoxification. In order to determine prevalence of use in cannabis smokers, a population at high risk for SC use, we obtained data on demographics of SC users, frequency of use, and adverse effects over a 3.5-year period (2012–2015) in the New York City metropolitan area, a region with a recent history of high SC use. While controlled studies on the physiological and behavioral effects of SCs are lacking, it is clear that risks associated with using these drugs pertain not only to the unpredictable and severe nature of acute intoxication but also to the effects of long-term, chronic use. Recent reports in the literature parallel findings from our survey, indicating that there is a subset of people who use SCs daily. Although withdrawal has not been systematically characterized and effective treatments have yet to be elucidated, some symptom relief has been reported with benzodiazepines and the atypical antipsychotic, quetiapine. Given the continued use and abuse of SCs, empirical studies characterizing (1) SCs acute effects, (2) withdrawal upon cessation of use, and (3) effective treatment strategies for SC use disorder are urgently needed.     

In-shoe center of pressure: Indirect force plate vs. direct insole measurement

BackgroundIn-shoe center of pressure (COP) measurement is essential in biomechanics. COP can be measured directly utilizing pressure-sensitive insoles, or calculated indirectly via force plate-generated data. While the latter does not require the use of additional measurement hardware (shoe insoles), its precision at calculating in-shoe COP has not been determined. Our purpose was to ascertain the precision of force plate in-shoe COP calculations and enhance their accuracy through a mathematical algorithm.MethodsTwelve male students participated in the study. In-shoe COP was measured synchronously via the Pedar-X insole system and AMTI force plates, comparing the measurements of both systems. A mathematical algorithm was created to improve agreement between the systems and comparisons were recalculated.ResultsThe two methods showed different measurements of in-shoe COP. The medio-lateral (ML) and anterior-posterior (AP) Pearson correlation coefficients between systems were 0.44 ± 0.35 and 0.99 ± 0.01, and the ML and AP RMS errors were 6.3 ± 3.0 mm and 43.0 ± 12.5 mm, respectively. Using a mathematical algorithm, the differences between the measurements of each system could be reduced significantly (all P < 0.001).ConclusionsWithout adjustment, force plates give an approximate location of the COP. Using an adjustment model greatly improves the accuracy of the COP trajectory during stance.     

Behavioral Problems of Seniors in an Emergency Department

Background

Behavioral disorders are frequent in seniors with cognitive impairments. The ailment responsible for presentation to the Emergency Department (ED), in combination with preexisting conditions, can bring about a temporary cognitive disturbance or worsen an existing cognitive disturbance, thus increasing the frequency of behavioral disorders.

Study Objectives

The purpose of this research was to investigate whether there is any connection between pain, cognitive impairment, time in the ED, presence or absence of a supportive escort, and behavioral disorders exhibited by a senior.

Methods

The study sample consisted of 140 seniors aged 69 years and older who visited the ED. Data collected included personal data, presence or absence of an escort, length of stay in the ED, and formal reproducible evaluation of cognition, behavior, and pain.

Results

Behavioral disorders were found to be present in 18% of the total sample and in 25% of the group of seniors who suffered from cognitive impairment. The presence of cognitive impairment was found to increase by almost sevenfold the risk of a behavioral disorder. Presence of severe pain increased the risk of a behavioral disorder even more (odds ratio 63). Seniors with cognitive impairment who spent a longer-than-average time period in the ED exhibited behavioral disorders that were more severe than disorders in seniors without cognitive impairment. There was no moderating effect on behavioral disturbances by the presence of a supportive escort observed.

Conclusions

The findings of this study suggest that the risk of behavioral disorders in seniors attending the ED may be predicted by screening them for cognitive impairment and pain, and by monitoring the time period they are in the ED.     

Pharmacology of the novel antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2): observation of a U-shaped dose-response curve in several preclinical models of angiogenesis and tumor growth.

PURPOSE: ATN-161 (Ac-PHSCN-NH(2)) is an integrin-binding peptide that is currently in phase II trials in cancer patients. This peptide has been shown to have antitumor activity in a number of different preclinical models. EXPERIMENTAL DESIGN: In this study, we examined the binding, biodistribution, and dose and biomarker response of ATN-161 in several animal models. RESULTS: ATN-161 bound to the beta subunit of a number of different integrins implicated in tumor growth and progression, which depended on its cysteine thiol. The peptide had antiangiogenic activity in the Matrigel plug model, and this activity could be reversed by inhibitors of protein kinase A, an effector of alpha(5)beta(1)-dependent angiogenesis. A labeled analogue of ATN-161, ATN-453, localized to neovessels but not to preexisting vasculature in vivo. The half-life of the peptide when localized to a tumor was much longer than in plasma. Dose-response studies in the Matrigel plug model of angiogenesis or a Lewis lung carcinoma model of tumor growth showed a U-shaped dose-response curve with 1 to 10 mg/kg given thrice a week, being the optimal dose range of ATN-161. Two additional pharmacodynamic models of angiogenesis (dynamic contrast-enhanced magnetic resonance imaging and measurement of endothelial cell progenitors) also revealed U-shaped dose-response curves. CONCLUSIONS: The presence of a U-shaped dose-response curve presents a significant challenge to identifying a biologically active dose of ATN-161. However, the identification of biomarkers of angiogenesis that also exhibit this same U-shaped response should allow the translation of those biomarkers to the clinic, allowing them to be used to identify the active dose of ATN-161 in phase II studies.     

Hereditary branching enzyme dysfunction in adult polyglucosan body disease: a possible metabolic cause in two patients.

We describe 2 unrelated patients with adult polyglucosan body disease (APBD) diagnosed by sural nerve biopsy. Both patients were offspring of consanguineous marriages. They presented clinically with late onset pyramidal tetraparesis, micturition difficulties, peripheral neuropathy, and mild cognitive impairment. Magnetic resonance imaging of the brain revealed extensive white matter abnormalities in both. In search of a possible metabolic defect, we evaluated glycogen metabolism in these patients and their clinically unaffected children. Branching enzyme activity in the patients' polymorphonuclear leukocytes was about 15% of control values, whereas their children displayed values of 50 to 60%, suggesting a possible autosomal recessive mode of transmission. This is the first report of an inherited metabolic defect in patients with adult polyglucosan body disease. We suggest that branching enzyme dysfunction may be implicated in the pathogenesis of some patients with adult polyglucosan body disease.     

Comprehensive in vitro pro‐arrhythmic assays demonstrate that omecamtiv mecarbil has low pro‐arrhythmic risk

Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro‐arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow‐up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half‐maximal inhibitory concentration [IC₅₀] = 125.5 µM) and Nav1.5 and Cav1.2 assays (IC₅₀ > 300 µM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro‐arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro‐arrhythmia risk at OM concentration up to 30 µM (100‐fold the effective free therapeutic plasma concentration). In the isolated canine PF assay, OM shortened AP duration (APD)₆₀ and APD₉₀ significantly from 3 to 30 µM. In perfused IRH, ventricular repolarization (corrected QT and corrected JT intervals) was decreased significantly at greater than or equal to 1 µM OM. In summary, the comprehensive proarrhythmic assessment in human and non‐rodent cardiac models provided data indicative that OM did not delay ventricular repolarization at therapeutic relevant concentrations, consistent with clinical findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A new therapeutic agent, omecamtiv mecarbil (OM), increases cardiac contractility by prolonging systolic ejection time, however, there is no published data assessing its pro‐arrhythmic risks.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Pro‐arrhythmic risk assessment of OM in in vitro and ex vivo safety pharmacology models compliant with International Conference on Harmonization S7B guideline and Comprehensive In Vitro Proarrhythmia Assay initiative.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Comprehensive in vitro pro‐arrhythmic risk assays demonstrate that OM has low pro‐arrhythmic risk and translate into clinical safety observations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Low pro‐arrhythmic risks consistently identified in preclinical in vitro models translate well into clinical observations (i.e., negative preclinical pro‐arrhythmic findings can predict negative clinical outcomes).     

Effects of Acute Oral Naltrexone on the Subjective and Physiological Effects of Oral D-Amphetamine and Smoked Cocaine in Cocaine Abusers

Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D-AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3-week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence.     

Comparison of the Analgesic Effects of Dronabinol and Smoked Marijuana in Daily Marijuana Smokers

Recent studies have demonstrated the therapeutic potential of cannabinoids to treat pain, yet none have compared the analgesic effectiveness of smoked marijuana to orally administered Δ⁹-tetrahydrocannabinol (THC; dronabinol). This randomized, placebo-controlled, double-dummy, double-blind study compared the magnitude and duration of analgesic effects of smoked marijuana and dronabinol under well-controlled conditions using a validated experimental model of pain. Healthy male (N=15) and female (N=15) daily marijuana smokers participated in this outpatient study comparing the analgesic, subjective, and physiological effects of marijuana (0.00, 1.98, or 3.56% THC) to dronabinol (0, 10, or 20 mg). Pain response was assessed using the cold-pressor test (CPT): participants immersed their left hand in cold water (4 °C), and the time to report pain (pain sensitivity) and withdraw the hand from the water (pain tolerance) were recorded. Subjective pain and drug effect ratings were also measured as well as cardiovascular effects. Compared with placebo, marijuana and dronabinol decreased pain sensitivity (3.56% 20 mg), increased pain tolerance (1.98% 20 mg), and decreased subjective ratings of pain intensity (1.98, 3.56% 20 mg). The magnitude of peak change in pain sensitivity and tolerance did not differ between marijuana and dronabinol, although dronabinol produced analgesia that was of a longer duration. Marijuana (1.98, 3.56%) and dronabinol (20 mg) also increased abuse-related subjective ratings relative to placebo; these ratings were greater with marijuana. These data indicate that under controlled conditions, marijuana and dronabinol decreased pain, with dronabinol producing longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective effects than marijuana.