Abstract Context Osteoarthritis (OA) is a common cause of chronic pain, particularly in the older population. Modern approaches to the management of OA pain recommend tailoring treatment to the ...individual. This study examines treatment options for OA pain in the form of low-dose transdermal and sublingual opioid analgesia. Objectives The aims of this trial were to compare the efficacy and tolerability of seven-day, low-dose transdermal buprenorphine patches ( BuTrans® , Napp Pharmaceuticals Limited UK) with sublingual buprenorphine (Temgesic® , Schering-Plough Limited UK) in patients with moderate to severe pain caused by OA of the hip(s) and/or knee(s), and to establish analgesic equivalence of the two products. Methods Two hundred forty-six patients with OA pain in the hip(s) and/or knee(s) were enrolled in this randomized, double-blind, parallel-group study; 110 completed the study. Patients were randomized to receive transdermal buprenorphine patches (5, 10, and 20 μg/hour) or sublingual buprenorphine (200 and 400 μg tablets). Their medication was titrated to pain control and they were treated for up to seven weeks. The main outcome measures were pain intensity (primary outcome), sleep disturbance, quality of life, and safety assessments. Results Patients' Box Scale-11 pain scores decreased between entry and assessment in both treatment groups. During the 28-day assessment period, the estimated mean treatment differences (95% confidence intervals) were 0.00 (−0.68,0.69), −0.11 (−0.85,0.63), and −0.13 (−0.95,0.68), for the morning, midday, and evening scores, respectively. All the confidence intervals were within the prespecified limits for equivalence (−1.5, 1.5). Use of escape medication was low. In both treatment groups, sleep disturbance caused by pain decreased between entry and assessment. Patients' quality of life improved during the study. Significantly fewer patients receiving the transdermal buprenorphine patches reported nausea ( P = 0.035), dizziness ( P = 0.026), and vomiting ( P = 0.039). Conclusion In conclusion, seven-day, low-dose transdermal buprenorphine patches are as effective as sublingual buprenorphine, with a better tolerability profile.
Liquid chromatography tandem mass spectrometry (LC-MS/MS) has been shown to be a viable tool for preclinical pharmacokinetic (PK) analysis of monoclonal antibody (mAb) therapeutics. This work ...describes free and total PK assays for the mAb PF-00547,659 in serum of ulcerative colitis patients in a First-In-Human study Vermeire, S. et al. Gut 2011, 60 (8), 1068–1075. The assay to measure free PF-00547,659 used immuno-enrichment with a biotinylated anti-idiotypic antibody and streptavidin magnetic beads. The total assay used enrichment by protein G magnetic beads. Following elution of PF-00547,659 from the beads, addition of an extended sequence stable isotope labeled peptide and trypsin digestion, a proteotypic peptide derived from the CDR region of the light chain of PF-00547,659 was quantified by LC-MS/MS. The free assay had a calibration range from 7.03 ng/mL to 450 ng/mL. The assay was precise and accurate with interbatch imprecision <16.5%, and interbatch inaccuracy <13.7% at all concentrations investigated during assay qualification. Results from LC-MS/MS methodologies are compared with historical immunoassay data originally acquired during the course of the clinical study. PK parameter estimates were highly correlated between the two analytical approaches. This work provides precedence that immunoaffinity LC-MS/MS can effectively be used to measure the serum concentrations of mAb therapeutics in clinical studies.
A novel thiophene substituted isoindigo and its copolymer with benzothiadiazole have been synthesized. The polymer with low lying LUMO energy levels exhibits excellent ambipolar behavior in field ...effect transistors with both hole and electron mobilities recorded over 0.1 cm(2) V(-1) s(-1).
The brain's unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, reactive nitrogen species ...(RNS) production, and antioxidant defense mechanisms. This review explores the factors contributing to the brain's vascular tone's vulnerability in the presence of oxidative damage, which can be of clinical interest in critically ill patients or those presenting acute brain injuries. The brain's high metabolic rate and inefficient electron transport chain in mitochondria lead to significant ROS generation. Moreover, non-replicating neuronal cells and low repair capacity increase susceptibility to oxidative insult. ROS can influence cerebral vascular tone and permeability, potentially impacting cerebral autoregulation. Different ROS species, including superoxide and hydrogen peroxide, exhibit vasodilatory or vasoconstrictive effects on cerebral blood vessels. RNS, particularly NO and peroxynitrite, also exert vasoactive effects. This review further investigates the neuroprotective effects of antioxidants, including superoxide dismutase (SOD), vitamin C, vitamin E, and the glutathione redox system. Various studies suggest that these antioxidants could be used as adjunct therapies to protect the cerebral vascular tone under conditions of high oxidative stress. Nevertheless, more extensive research is required to comprehensively grasp the relationship between oxidative stress and cerebrovascular tone, and explore the potential benefits of antioxidants as adjunctive therapies in critical illnesses and acute brain injuries.
Evolution results from the interaction of stochastic and deterministic processes that create a web of historical contingency, shaping gene content and organismal function. To understand the scope of ...this interaction, we examine the relative contributions of stochasticity, determinism, and contingency in shaping gene inactivation in 34 lineages of endosymbiotic bacteria, Sodalis, found in parasitic lice, Columbicola, that are independently undergoing genome degeneration. Here we show that the process of genome degeneration in this system is largely deterministic: genes involved in amino acid biosynthesis are lost while those involved in providing B-vitamins to the host are retained. In contrast, many genes encoding redundant functions, including components of the respiratory chain and DNA repair pathways, are subject to stochastic loss, yielding historical contingencies that constrain subsequent losses. Thus, while selection results in functional convergence between symbiont lineages, stochastic mutations initiate distinct evolutionary trajectories, generating diverse gene inventories that lack the functional redundancy typically found in free-living relatives.
The literature indicates that individuals with diabetes do not easily adopt smoking cessation interventions. Given that the success of such interventions depends on patient involvement and attitudes, ...assessing intervention acceptability, including patient satisfaction and perceived usefulness, is crucial before implementing a smoking cessation intervention. This paper reports the preliminary validation of the satisfaction and perceived usefulness questionnaires for evaluating smoking cessation interventions among individuals with diabetes.
Validity study.
The satisfaction questionnaire contained eight statements while the perceived usefulness questionnaire had fourteen; both rated on a 5-point Likert scale. Content validation involved five tobacco cessation facilitators rating item relevance using a 4-point ordinal rating scale, suggesting improvements. The questionnaires were also translated into Maltese for local use and assessed for translation validity using a similar scale. Unanimous agreement among experts was required for item relevance and equivalence. Thirty-four individuals with type 1 or type 2 diabetes, attending a diabetes-specific smoking cessation intervention, received either the Maltese or English versions of the questionnaires. Internal consistency was measured using Cronbach's alpha.
After two rounds of content validation, the experts unanimously agreed on item relevance and conceptual equivalence. Fifteen and sixteen participants completed the Maltese and English versions of the questionnaires, respectively. Both questionnaires’ versions were found to have a high internal consistency (>0.8).
These findings provide the initial validation of these instruments for assessing the acceptability of smoking cessation interventions among individuals with diabetes. Further validation in different settings using a larger sample is suggested.
Background Atherogenesis represents an active inflammatory process with leucocytes playing a major role. An elevated white blood cell count has been shown to be predictive of death in coronary artery ...disease patients. The aim of this study was to examine the predictive ability of neutrophil count and neutrophil/lymphocyte ratio for predicting survival in patients with critical lower limb ischemia (CLI). Methods All patients admitted to a single vascular unit with CCLI were identified prospectively over a 2-year period starting from January 2005. Patient demographics, clinical history, comorbidity, and risk factors for peripheral vascular disease were documented. The white blood count and differential cell count at admission was recorded. Overall, patient mortality was studied as the primary outcome. Results One hundred forty-nine patients were identified, with a median age of 72 years (Interquartile range IQR, 65.7-81). A neutrophil-lymphocyte ratio (NLR) of ≥5.25 was taken as the cutoff, based upon the receiver-operating-characteristic.The median follow up was 8.7 months (IQR, 3.1-16). During the follow-up period, there have been 62 deaths (43.4%). An elevated neutrophil/lymphocyte ratio and a high troponin level (>0.1) were found to be the only two factors independently associated with shorter survival on multivariate analysis using the Cox proportional hazards model. Conclusions This study suggests that an elevated NLR can identify a poor-risk subset of patients among those being treated for critical limb ischemia. This simple, inexpensive test may, therefore, add to risk stratification of these high-risk patients.
Autism spectrum condition is associated with co-occurring physical health conditions and premature mortality. Autistic people experience multiple barriers to accessing healthcare. This study ...investigated autistic people’s experiences of healthcare and professionals’ experiences of providing healthcare to autistic people. Focus groups with 11 autistic people and one supporter, and 15 one-to-one interviews with healthcare professionals were completed. Nine themes emerged from the autistic participants’ data and eight themes emerged from the health professionals’ data. Three themes were identified by both groups: healthcare contacts (for improving the patient–provider relationship), making reasonable adjustments to healthcare (e.g. providing alternative places to wait for an appointment) and autism diagnosis. Autistic participants discussed the role of cognitive factors in the success of healthcare visits (such as rehearsing an anticipated conversation with the clinician the night before an appointment) and clinicians described system-level constraints that may affect healthcare delivery (such as time limits on appointments). This study identified inexpensive changes that health professionals and managers can make to improve healthcare access for autistic people.
Lay abstract
Research has shown that on average, autistic people are more likely to die earlier than non-autistic people, and barriers can stop autistic people accessing healthcare. We carried out a study where we interviewed healthcare professionals (including doctors and nurses), and held discussion groups of autistic people. Our results highlighted several key points: seeing the same professional is important for autistic people and clinicians; both clinicians and autistic people think making adjustments to healthcare is important (and often possible); autistic people process information in a different way and so may need extra support in appointments; and that clinicians are often constrained by time pressures or targets.
Background
The delta opioid receptor (DOR) has been identified as a therapeutic target for migraine, with DOR agonists exhibiting low abuse potential compared with conventional µ-opioid agonists. ...TRV250 is a novel small molecule agonist of the DOR that is preferentially selective for G-protein signaling, with relatively little activation of the β-arrestin2 post-receptor signaling pathway. This selectivity provides reduced susceptibility to proconvulsant activity seen with non-selective DOR agonists. TRV250 significantly reduced nitroglycerin-evoked hyperalgesia in rodents, indicating a potential utility in acute migraine without the risk of seizure activity or abuse potential.
Objective
This trial evaluated the safety, tolerability, and pharmacokinetics of ascending dose levels of TRV250 administered subcutaneously (SC) and the relative bioavailability of TRV250 administered orally compared with SC administration.
Methods
This was a two-part, single ascending dose study. Part A included four cohorts of healthy adults (
N
= 38). Each cohort was dosed on three occasions (placebo and two different dose levels of TRV250, allocated in randomized order and administered by SC route). In Part B, a single cohort of nine subjects received an oral dose of either TRV250 (
n
= 7) or placebo (
n
= 2) in a fed or fasted state. Serial blood samples were obtained for pharmacokinetic determination across a 24-h post-dose period. Safety assessments included clinical laboratory measures, vital signs, 12-lead electrocardiogram (ECG), and electroencephalogram (EEG) pre- and post-dosing.
Results
TRV250 was well tolerated. There were no serious adverse events (SAEs), and all AEs were mild in severity. Injection-site reactions and headache were the most common AEs. One subject was withdrawn from the study due to a TRV250-related AE of postural orthostatic tachycardia. There were no clinically relevant changes in physical examination, hematology, clinical chemistry, urinalysis, suicidal ideation, or vital signs, with the exception of orthostatic changes in some subjects. No subject experienced abnormalities in EEGs or experienced a change from baseline in heart-rate-corrected QT interval (QTcF) > 60 ms, or an absolute QTcF interval > 480 ms at any post-dosing observation. Peak and total plasma exposure to TRV250 increased in a dose-proportional manner following 0.1–30 mg SC doses, with the mean half-life ranging from 2.39 to 3.76 h. Oral bioavailability of TRV250 ranged from 14% (fasting) to 19% (fed) relative to SC dosing, while administration with food increased the AUC but decreased the rate of absorption as reflected by a modest delay in median time to maximum concentration and a slight reduction in maximum concentration.
Conclusion
The findings from the first-in-human study support further evaluation of TRV250, a G-protein selective DOR agonist, in the treatment of acute migraine.
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