Liability For Use Research Articles

Bis-Cyclic Guanidine Heterocyclic Peptidomimetics as Opioid Ligands with Mixed μ-, κ- and δ-Opioid Receptor Interactions: A Potential Approach to Novel Analgesics.

The design and development of analgesics with mixed-opioid receptor interactions has been reported to decrease side effects, minimizing respiratory depression and reinforcing properties to generate safer analgesic therapeutics. We synthesized bis-cyclic guanidine heterocyclic peptidomimetics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for the mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR) across the series, with compound 1968-22 displaying good affinity for all three receptors. Central intracerebroventricular (i.c.v.) administration of 1968-22 produced dose-dependent, opioid receptor-mediated antinociception in the mouse 55 °C warm-water tail-withdrawal assay, and 1968-22 also produced significant antinociception up to 80 min after oral administration (10 mg/kg, p.o.). Compound 1968-22 was detected in the brain 5 min after intravenous administration and was shown to be stable in the blood for at least 30 min. Central administration of 1968-22 did not produce significant respiratory depression, locomotor effects or conditioned place preference or aversion. The data suggest these bis-cyclic guanidine heterocyclic peptidomimetics with multifunctional opioid receptor activity may hold potential as new analgesics with fewer liabilities of use.

Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use.

Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED50 (and 95% C.I.) value of 13.2 (7.42–28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.

Liability for Use of Artificial Intelligence in Medicine

Liability for Use of Artificial Intelligence in Medicine

The standard of liability in claims for misuse of private information

ABSTRACT This article attempts to identify a standard of liability for use in claims for misuse of private information (MPI). It highlights current uncertainty over this issue following the decision of the Supreme Court in Lloyd v Google LLC. It considers whether the comments of Lord Leggatt in Lloyd are compatible with those made in earlier MPI decisions and argues that the standard applicable remains an open question. In formulating a proposed standard, the article considers issues arising under the Human Rights Act 1998 and is informed by the recommendations of the Australian Law Reform Commission in its review of Australian privacy law. It is suggested that the appropriate standard for the MPI tort ought to be one of ‘quasi-strict’ liability, meaning that liability could, in certain cases, be strict. Whether a defendant would be found to be strictly liable should be determined through the reasonable expectation of privacy test.

Analysis of results of survey on disciplinary liability for use of athletes and methods prohibited from the perspective of contemporary challenges of sport

Artykuł ten poświęcony jest analizie badań własnych przeprowadzonych w formie ankietowania na temat dyscyplinarnej odpowiedzialności sportowców za stosowanie środków dopingowych. Dopingiem jest zażywanie substancji zabronionych, a odpowiedzialność za stosowanie środków dopingowych jest odpowiedzialnością dyscyplinarną. Motywem przewodnim dla przeprowadzonego badania jest przypadek tenisistki Marii Sharapowej, która użyła Meldonium. Dla celu tego artykułu został przeprowadzony sondaż obejmujący 580 respondentów. Analiza ma służyć uzyskaniu opinii, czy respondencji zdają sobie sprawę co stanowi doping w sporcie i jakie są kary za jego wykorzystanie w sporcie wyczynowym. Istotne jest czy respondenci negatywnie oceniają zawodników stosujących doping jak Szarapowa i czy chcą surowszych kar za stosowanie środków dopingowych. Badanie przekazuje ważne informacje zawierające opinie o stosowaniu środków dopingowych. Ważne, że pomimo coraz większej wykrywalności przypadków stosowania środków dopingowych na świecie, to stosowanie dopingu jest częste wśród sportowców. Tymczasem niezatwierdzone substancje, które pojawiają się na rynku, stają się trudniejsze do wykrycia i są coraz bardziej niebezpieczne dla sportowca. Abstract This paper concerns the analysis of disciplinary responsibility of sportsman for doping. Responsibility for doping has a constructive character of disciplinary, but in exceptional circumstances, the nature of legal liability under the Penal Code. The motive to carry out the research was doping of tennis player - Maria Sharapova and she used Meldonium. For the purpose of the article was carried out a survey of 580 people. The study showed that despite the fact, that the respondents are interested in sports and amateur practice, it is not exactly are aware of what is doping in sport, and what are the penalties for its use in professional sport. People negatively evaluate such sportsman as Sharapova and they want greater penalties for doping. The survey is an important exploration opinion on doping. Despite more and more serious cases of doping in the world, and still these subject is treated marginally and slowly becomes a real plague among sportsman. Non - approved substances that appear on the market, are becoming harder to detect, more and more dangerous for the sportsman.

Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.

Background and purposeThe κ receptor has a central role in modulating neurotransmission in central and peripheral neuronal circuits that subserve pain and other behavioural responses. Although κ receptor agonists do not produce euphoria or lead to respiratory suppression, they induce dysphoria and sedation. We hypothesized that brain‐penetrant κ receptor ligands possessing biased agonism towards G protein signalling over β‐arrestin2 recruitment would produce robust antinociception with fewer associated liabilities.Experimental approachTwo new diphenethylamines with high κ receptor selectivity, HS665 and HS666, were assessed following i.c.v. administration in mouse assays of antinociception with the 55°C warm‐water tail withdrawal test, locomotor activity in the rotorod and conditioned place preference. The [35S]‐GTPγS binding and β‐arrestin2 recruitment in vitro assays were used to characterize biased agonism.Key resultsHS665 (κ receptor agonist) and HS666 (κ receptor partial agonist) demonstrated dose‐dependent antinociception after i.c.v. administration mediated by the κ receptor. These highly selective κ receptor ligands displayed varying biased signalling towards G protein coupling in vitro, consistent with a reduced liability profile, reflected by reduced sedation and absence of conditioned place aversion for HS666.Conclusions and implicationsHS665 and HS666 activate central κ receptors to produce potent antinociception, with HS666 displaying pharmacological characteristics of a κ receptor analgesic with reduced liability for aversive effects correlating with its low efficacy in the β‐arrestin2 signalling pathway. Our data provide further understanding of the contribution of central κ receptors in pain suppression, and the prospect of dissociating the antinociceptive effects of HS665 and HS666 from κ receptor‐mediated adverse effects.

Уголовная ответственность за использование в отношении спортсмена допинга

The article is devoted to analysis of art. 230² of the Criminal Code of the Russian Federation establishing liability for use of the substances and (or) methods prohibited in sports in respect of a sportsman.

Analysis of results of survey on disciplinary liability for use of athletes and methods prohibited from the perspective of contemporary challenges of sport

Analysis of results of survey on disciplinary liability for use of athletes and methods prohibited from the perspective of contemporary challenges of sport

Adolescent Life History Strategy in the Intergenerational Transmission and Developmental Stability of Substance Use

Research suggests that fast life history strategy (LHS) may be a primary driver of substance use among young adults. However, a recent study reported that (a) young adult fast LHS did not subsume all theorized indicators of LHS during this period and (b) fast LHS among parents did not predict young adult fast LHS or liability for use of common substances. In this study, we used structural equations and national data to test whether these findings generalized to adolescence. In addition, given that LHS and substance use share genetic and neuropsychological bases, we examined whether fast LHS could explain the developmental stability of substance use. Overall, our results extend the findings discussed above and suggest that fast LHS fully explains the developmental stability of substance use among youth. We discuss implications for life history models, research applying life history theory and substance use, and substance abuse prevention and treatment.

Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at μ (MOR), δ (DOR), and κ (KOR) Opioid Receptors.

In the development of analgesics with mixed-opioid agonist activity, peripherally selective activity is expected to decrease side effects, minimizing respiratory depression and reinforcing properties generating significantly safer analgesic therapeutics. We synthesized diazaheterocyclics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for μ (MOR), δ (DOR), and κ (KOR) opioid receptors across the series, with the diimidazodiazepine 14 (2065-14) displaying good affinity for DOR and KOR. Central (icv), intraperitoneal (ip), or oral (po) administration of 14 produced dose-dependent, opioid-receptor mediated antinociception in the mouse, as determined from a 55 °C warm-water tail-withdrawal assay. Only trace amounts of compound 14 was found in brain up to 90 min later, suggesting poor BBB penetration and possible peripherally restricted activity. Central administration of 14 did not produce locomotor effects, acute antinociceptive tolerance, or conditioned-place preference or aversion. The data suggest these diazaheterocyclic mixed activity opioid receptor agonists may hold potential as new analgesics with fewer liabilities of use.

Beyond the responsibility gap. Discussion note on responsibility and liability in the use of brain-computer interfaces

The article shows where the argument of responsibility-gap regarding brain-computer interfaces acquires its plausibility from, and suggests why the argument is not plausible. As a way of an explanation, a distinction between the descriptive third-person perspective and the interpretative first-person perspective is introduced. Several examples and metaphors are used to show that ascription of agency and responsibility does not, even in simple cases, require that people be in causal control of every individual detail involved in an event. Taking up the current debate on liability in BCI use, the article provides and discusses some rules that should be followed when potentially harmful BCI-based devices are brought from the laboratory into everyday life.

AACVPR/ACCF/AHA 2010 Update: Performance Measures on Cardiac Rehabilitation for Referral to Cardiac Rehabilitation/Secondary Prevention Services

Over the past decade, there has been an increasing awareness that the quality of medical care delivered in the United States is variable. In its seminal document dedicated to characterizing deficiencies in delivering effective, timely, safe, equitable, efficient, and patient-centered medical care, the Institute of Medicine described a quality “chasm”.1 Recognition of the magnitude of the gap between the care that is delivered and the care that ought to be provided has stimulated interest in the development of measures of quality of care and the use of such measures for the purposes of quality improvement and accountability. Consistent with this national focus on healthcare quality, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have taken a leadership role in developing measures of the quality of care for cardiovascular disease (CVD) in several clinical areas Table 1. The ACCF/AHA Task Force on Performance Measures was formed in February 2000 and was charged with identifying the clinical topics appropriate for the development of performance measures and assembling writing committees composed of clinical and methodological experts. When appropriate, these committees include representatives from other organizations with an interest in the clinical topic under consideration. The committees are informed about the methodology of performance measure development and are instructed to construct measures for use both prospectively and retrospectively, rely upon easily documented clinical criteria, and where appropriate, incorporate administrative data. The data elements required for the performance measures are linked to existing ACCF/AHA clinical data standards to encourage uniform measurements of …

Potential liability for use of expert systems : Michael C. Gemignani, IDEA (vol. 29, no. 2), pp. 120–127

Potential liability for use of expert systems : Michael C. Gemignani, IDEA (vol. 29, no. 2), pp. 120–127

Should Courts Answer Questions? Does Statutory Authority to Build Confer Immunity From Liability for Use?

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Liability in Use of Investigational Drugs

RECENT DEVELOPMENTS, including the growth of clinical research centers, the new regulations of the Food and Drug Administration (FDA), and the publicity surrounding the reported adverse reactions to thalidomide have prompted this examination of the moral and legal entanglements facing the clinical investigator. Purpose of Clinical Investigator The primary purpose of clinical investigation is to produce scientifically reliable data which will serve to answer specific questions or, simply, to satisfy the investigator's scientific curiosity. Any such investigation, therefore, must be done within the framework of a rational experimental design. Moreover, since the purpose of a drug investigation is to acquire and interpret reliable data which may lead to the proper application of new therapeutic agents, it must include basic, clinical, and therapeutic studies—all of these are necessary if medicine is to advance in knowledge and wisdom. Finally, it is not necessarily the purpose of the clinical investigator to avoid controversy,

Conditional Sales. Repossession by Vendor upon Default as Rescission. Extent of Vendee's Liability for Use

Conditional Sales. Repossession by Vendor upon Default as Rescission. Extent of Vendee's Liability for Use

Executors and Administrators. Administration Bonds. Surety's Liability for Use of Funds of Third Party as Assets of Decedent

Executors and Administrators. Administration Bonds. Surety's Liability for Use of Funds of Third Party as Assets of Decedent

Torts. Negligence. Liability for Use of Dangerous Agency

Torts. Negligence. Liability for Use of Dangerous Agency