Effect profile of paracetamol, Δ9-THC and promethazine using an evoked pain test battery in healthy subjects.

BACKGROUND: A battery of evoked pain tasks (PainCart) was developed to investigate the pharmacodynamic properties of novel analgesics in early-phase clinical research. As part of its clinical validation, compounds with different pharmacological mechanisms of actions are investigated. The aim was to investigate the analgesic effects of classic and nonclassic analgesics compared to a sedating negative control in a randomized placebo-controlled crossover study in 24 healthy volunteers using the PainCart. METHODS: The PainCart consisted of pain tasks eliciting electrical, pressure, heat, cold and inflammatory pain. Subjective scales for cognitive functioning and psychotomimetic effects were included. Subjects were administered each of the following oral treatments: paracetamol (1000 mg), Δ9-THC (10 mg), promethazine (50 mg) or matching placebo. Pharmacodynamic measurements were performed at baseline and repeated up to 10 h postdose. RESULTS: Paracetamol did not show a significant reduction in pain sensation or subjective cognitive functioning compared to placebo. Promethazine induced a statistically significant reduction in PTT for cold pressor and pressure stimulation. Furthermore, reduced subjective alertness was observed. Δ9-THC showed a statistically significant decrease in PTT for electrical and pressure stimulation. Δ9-THC also demonstrated subjective effects, including changes in alertness and calmness, as well as feeling high and psychotomimetic effects. CONCLUSIONS: This study found a decreased pain tolerance due to Δ9-THC and promethazine, or lack thereof, using an evoked pain task battery. Pain thresholds following paracetamol administration remained unchanged, which may be due to insufficient statistical power. We showed that pain thresholds determined using this pain test battery are not driven by sedation. SIGNIFICANCE: The multimodal battery of evoked pain tasks utilized in this study may play an important role in early-phase clinical drug development. This battery of pain tasks is not sensitive to the effects of sedation alone, and thus suitable to investigate the analgesic potential of novel analgesic compounds.

No evidence of potentiation of buprenorphine by milnacipran in healthy subjects using a nociceptive test battery.

BACKGROUND: Serotonin-norepinephrine reuptake inhibitors inhibit the reuptake of serotonin and noradrenalin and are used in the treatment of neuropathic pain. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of µ-opioid receptor agonists. This study hypothesized that co-administration of milnacipran and buprenorphine would have a synergistic effect in evoked pain models in healthy subjects. METHODS: This was a randomized double-blinded, placebo-controlled, four-way cross-over, multiple dose clinical trial to investigate the analgesic effects of buprenorphine (placebo, 0.5, 1 and 3 µg/kg) in combination with milnacipran (placebo, 25 and 50 mg) in healthy subjects. RESULTS: 11 healthy men were enrolled in the study. Buprenorphine alone showed a dose-response relationship indicative of anti-nociception in the pain tests. Following milnacipran administration, no changes were seen in the pharmacodynamic measurements for pain, psychomotor function, body stability or eye movements. For the electrical tests, cold pressor test and pressure pain test, buprenorphine alone was superior when compared with buprenorphine plus milnacipran. No differences in pharmacodynamic variables, besides an increase in pupil/iris ratio, were observed after repeated administration of milnacipran 50 mg. Single and multiple doses of 25 or 50 mg milnacipran did not further potentiate the anti-nociceptive effects of buprenorphine. CONCLUSIONS: Buprenorphine showed dose-dependent effects consistent with its pharmacological profile. Milnacipran alone did not affect any of the pain variables. The combination of both buprenorphine and milnacipran did not potentiate or show a synergistic effect on the pain models used in this study. SIGNIFICANCE: Buprenorphine is known to be a potent opioid agonist. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of µ-opioid receptor agonists. Here, we found that buprenorphine showed a dose-dependent analgesic effect, but that no potentiation or synergy on a battery of evoked pain tasks could be observed after co-administration of both milnacipran and buprenorphine.

Quantifying Beta-Galactosylceramide Kinetics in Cerebrospinal Fluid of Healthy Subjects Using Deuterium Labeling.

Therapeutics promoting myelin synthesis may enhance recovery in demyelinating diseases, such as multiple sclerosis. However, no suitable method exists to quantify myelination. The turnover of galactosylceramide (myelin component) is indicative of myelination in mice, but its turnover has not been determined in humans. Here, six healthy subjects consumed 120 mL 70% D2 O daily for 70 days to label galactosylceramide. We then used mass spectrometry and compartmental modeling to quantify the turnover rate of galactosylceramide in cerebrospinal fluid. Maximum deuterium enrichment of body water ranged from 1.5-3.9%, whereas that of galactosylceramide was much lower: 0.05-0.14%. This suggests a slow turnover rate, which was confirmed by the model-estimated galactosylceramide turnover rate of 0.00168 day-1 , which corresponds to a half-life of 413 days. Additional studies in patients with multiple sclerosis are needed to investigate whether galactosylceramide turnover could be used as an outcome measure in clinical trials with remyelination therapies.

Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects.

Previous reports have demonstrated greater antinociception following administration of a buprenorphine/naloxone combination compared to buprenorphine alone among healthy volunteers. The aim of the current investigation was to determine whether buprenorphine antinociception could be enhanced with the addition of ultra-low dose naltrexone, using a range of dose ratios. A repeated-measures, double-blind, cross-over trial was undertaken with 10 healthy participants. The effects of each buprenorphine:naltrexone ratio (100:1, 133:1, 166:1, and 200:1) on cold pressor tolerance time and respiration were compared to the effects of buprenorphine only. The 166:1 ratio was associated with significantly greater tolerance time to cold pressor pain than buprenorphine alone. Minimal respiratory depression and few adverse events were observed in all conditions. These findings suggest that, as previously described with naloxone, the addition of ultra-low dose naltrexone can enhance the antinociceptive effect of buprenorphine in humans. This potentiation is dose-ratio dependent and occurs without a concomitant increase in adverse effects.

Quasi-static and harmonic indentation of osteonal bone.

UNLABELLED: The purpose of the study was to compare Quasi-Static (QS) and harmonic (CSM) methods of indentation testing. Bone sections were obtained from mid-femoral diaphyses of dogs which received a pair of calcein labels. Labeled (n = 35) and unlabeled (n = 112) osteons were identified. Indentation modulus (IM) and hardness (H) for the CSM method were collected during the entire loading cycle to peak depth, while IM and H for QS method were calculated at a peak depth of 500 nm. RESULTS: The mean (SD) of the IM and H for labeled osteons were as follows: QS IM = 15.3 GPa (3.85) versus CSM IM = 14.7 GPa (3.58); P = .52 and QS H = .39 GPa (.171) versus CSM H = .42 GPa (.146); P = .32. The mean (SD) of the IM and H for unlabeled osteons were as follows: QS IM = 21.5 GPa (2.80) versus CSM IM = 20.6 GPa (2.53); P = .054 and QS H = .64 GPa (.117) versus CSM H = .70 GPa (.120); P = .017. There was no difference in IM and H for the two methods, except for H of the unlabeled osteons. In addition, for the CSM method, IM at 100 nm, 200 nm, 300 nm, 400 nm and 500 nm were not statistically significant different (P = .06). Bone is viscoelastic at an organ level. However, this component of its behavior was not detected at the length scale examined.

Influence of indenter tip geometry on elastic deformation during nanoindentation.

Nanoindentation with a Berkovich indenter is commonly used to investigate the mechanical behavior of small volumes of materials. To date, most investigators have made the simplifying assumption that the tip is spherical. In reality, indenter tips are much more complex. Here, we develop a new method to describe the tip shape using the experimentally determined area function of the indenter at small depths (0-100 nm). Our analysis accurately predicts the elastic load-displacement curve and allows the theoretical strength of a material to be determined from pop-in data. Application of our new method to single crystal Cr3Si shows that the predicted theoretical strengths are within 12% of the ideal strength G/2pi, where G is the shear modulus.

Bayesian analysis of a time series of counts with covariates: an application to the control of an infectious disease.

This paper presents a Bayesian analysis of a time series of counts to assess its dependence on an explanatory variable. The time series represented is the incidence of the infectious disease ESBL-producing Klebsiella pneumoniae in an Australian hospital and the explanatory variable is the number of grams of antibiotic (third generation) cephalosporin used during that time. We demonstrate that there is a statistically significant relationship between disease occurrence and use of the antibiotic, lagged by three months. The model used is a parameter-driven model in the form of a generalized linear mixed model. Comparison of models is made in terms of mean square error.

Dental students' attitudes toward smoking cessation guidelines.

Dentists can be effective in helping their patients achieve smoking cessation. To plan a didactic program, we explored the smoking cessation attitudes and practices of dental students and identified barriers to service provision in the dental setting. We assessed 244 fourth-year dental students at New York University College of Dentistry through a self-report survey. The instrument included a twenty-nine-item measure assessing attitudes towards tobacco-use counseling and adherence to National Cancer Institute tobacco cessation guidelines. The survey also assessed demographics, tobacco use history, and level of preparation to provide services. Generally, students endorsed tobacco prevention practices, but perceived barriers to service provision. Students provided counseling inconsistently, with 69 percent asking about smoking, 58 percent advising cessation, 24 percent offering assistance, and 22 percent providing followup on a routine basis. Those who provided more counseling were more likely to have undergone formal training in smoking cessation, did not feel time was a barrier to counseling, and had more favorable beliefs about dentists' role in promoting smoking cessation. Study findings indicate great receptivity among students as well as a critical need and opportunity to include comprehensive cessation counseling training in the dental curriculum.

The cancer patient with borderline personality disorder: suggestions for symptom-focused management in the medical setting.

Medically ill cancer patients with borderline personality disorder (BPD) face formidable emotional challenges as they cope with cancer diagnosis and treatment. The anxiety and discomfort associated with medical treatment can lead them to have difficulties with medical caregivers, distort reality for emotional protection, or exhibit outright aggression and self-destructiveness. Co-morbid substance abuse or a history of physical or sexual trauma may further complicate cancer treatment. These patients may be in particular need of symptom-focused psychotherapeutic management, which must include comprehensive assessment and treatment of psychiatric symptoms, measures to limit aggression and self-destructiveness, and staff education and support. These interventions can reduce patients' distress and maximize cancer treatment outcomes.

Host genetic factors influence disease progression in chronic hepatitis C.

Progressive hepatic fibrosis and cirrhosis develops in 20% to 30% of patients with chronic hepatitis C virus (HCV). We propose that host genetic factors influencing fibrogenesis may account for some of the variability in progression of this disease. In progressive fibrosis of other organs, particularly heart and kidney, production of the profibrogenic cytokine, transforming growth factor beta1 (TGF-beta1), may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system. The inheritance of polymorphisms in TGF-beta1, interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and genes of the renin-angiotensin system was examined in 128 patients with chronic HCV. The influence of genotypes on the stage of hepatic fibrosis was tested after adjustment for potential confounders (age, gender, alcohol consumption, portal inflammation, and steatosis), which may have independent effects on histological severity. The stage of fibrosis was 0 in 30 (23.4%), 1 in 44 (34.4%), 2 in 27 (21.1%), and 3 or 4 in 27 (21.1%). A statistically significant relationship was seen between inheritance of high TGF-beta1- and angiotensinogen (AT)-producing genotypes and the development of progressive hepatic fibrosis. This association persisted after correcting for potential confounders. Patients who inherited neither of the profibrogenic genotypes had no or only minimal fibrosis. Knowledge of these polymorphisms may have prognostic significance in patients with chronic HCV and may direct more aggressive therapy towards those patients with an increased risk of disease progression. The documentation of a significant relationship between AT genotype and fibrosis raises the novel suggestion that angiotensin II may be another mediator of extracellular matrix production in the liver.

A survey of smoking status and cancer risk perceptions among participants attending a hospital-based head and neck screening program.

Abstract Screening for head and neck cancer is underutilized. Given that lack of knowledge of the risk factors may partially account for screening underutilization. we surveyed subjective risk and knowledge of risk factors for head and neck cancer among 124 individuals who attended a free. hospital-based head and neck cancer screening. Few participants were current smokers. Most attendees perceived their risk as similar to others of their age and sex. Personal health habits comprised almost all of the risk-decreasing factors, yet less than half of the risk-increasing factors. generated. Personal habits were less frequently endorsed than factors such as pollution and heredity. Those who mentioned a risk behavior, or a family cancer history, reported higher subjective risk. Those who mentioned a personal health habit reported lower subjective risk. Results highlight needed efforts to increase screening among high-risk individuals through targeted education messages.

Motivating smoking cessation among dental patients: smokers' interest in biomarker testing for susceptibility to tobacco-related cancers.

This study examined interest in receiving biomarker testing for tobacco-related cancer susceptibility among 148 smokers seeking routine oral health care in a public dental clinic. Patients completed a brief, self-report survey assessing their smoking history, tobacco-related illness history, readiness to quit smoking, perceived risk and worry about cancer, and their interest in being tested for genetic susceptibility for tobacco-related cancers. Participants were socioeconomically and ethnically diverse, and were primarily long-standing, nicotine-dependent smokers. Most reported (83%) interest in biomarker feedback, and most (86%) understood that a certain genetic make-up could place them at increased risk for tobacco-related cancers. Those participants who felt that quitting smoking would reduce future cancer risk, were at least in the contemplation stage of quitting readiness, felt more worried and more at risk for developing cancer, women and younger smokers were more interested in genetic testing (all ps < 0.20). Multivariate logistic regression analyses indicated that gender and risk perceptions were associated with interest in testing. The public dental clinic setting holds potential for innovative smoking cessation interventions using personalized risk feedback.

Relationship between battery capacity and the delivery of shocks in prehospital defibrillators.

STUDY OBJECTIVE: Automatic external defibrillators (AED) have enabled the medical act of defibrillation to be performed in the community by a number of non-physician providers. However, these portable, battery-powered units are costly to maintain and service. This study examines the life of AED batteries and provides a battery replacement protocol. DESIGN: Prospective diagnostic testing of 191 field batteries to determine their ability to deliver shocks at 360 joule. SETTING: Ottawa General Hospital Paramedic Program. OUTCOMES: Using a battery analyzer, battery capacity and the number of shocks delivered were determined for each battery (at room temperature and in a controlled, refrigerated setting). In addition, the reliability of the testing method was assessed using the interclass correlation coefficient (ICC). RESULTS: High reliability of blinded technical assessment of the batteries was achieved (ICC = 0.85). A strong correlation between the battery's capacity and the number of shocks it can deliver was obtained. For example, a battery with a measured capacity of 75% is capable of delivering more than 30 consecutive 360 joule shocks. This compares to a battery with a capacity of 20%, which is capable of delivering only 12 consecutive 360 joule shocks. CONCLUSIONS: While manufacturers' recommendations on battery replacement always have been based on an assumed technical threshold, these recommendations are not based on individual battery performance. The system for testing batteries described in this paper, should provide significant cost savings and improve quality assurance within a prehospital AED program.