More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder.

Tobacco use is a persistent public health issue. It kills up to half its users and is the cause of nearly 90% of all lung cancers. The main psychoactive component of tobacco is nicotine, primarily responsible for its abuse-related effects. Accordingly, most pharmacotherapies for smoking cessation target nicotinic acetylcholine receptors (nAChRs), nicotine's major site of action in the brain. The goal of the current review is twofold: first, to provide a brief overview of the most commonly used behavioral procedures for evaluating smoking cessation pharmacotherapies and an introduction to pharmacokinetic and pharmacodynamic properties of nicotine important for consideration in the development of new pharmacotherapies; and second, to discuss current and potential future pharmacological interventions aimed at decreasing tobacco use. Attention will focus on the potential for allosteric modulators of nAChRs to offer an improvement over currently approved pharmacotherapies. Additionally, given increasing public concern for the potential health consequences of using electronic nicotine delivery systems, which allow users to inhale aerosolized solutions as an alternative to smoking tobacco, an effort will be made throughout this review to address the implications of this relatively new form of nicotine delivery, specifically as it relates to smoking cessation. SIGNIFICANCE STATEMENT: Despite decades of research that have vastly improved our understanding of nicotine and its effects on the body, only a handful of pharmacotherapies have been successfully developed for use in smoking cessation. Thus, investigation of alternative pharmacological strategies for treating tobacco use disorder remains active; allosteric modulators of nicotinic acetylcholine receptors represent one class of compounds currently under development for this purpose.

Nonpharmacological interventions for respiratory health in Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Respiratory dysfunction in Parkinson's disease (PD) is often an underdiagnosed and untreated impairment associated with the disease. Clinically, a reactive approach to respiratory morbidity is taken, rather than preventative approaches that address underlying impairment/s. This systematic review identifies the current evidence to support nonpharmacological interventions to improve respiratory impairments in individuals with PD. METHODS: The relevant literature was searched using a customised and systematic strategy. Randomised and nonrandomised control trials of nonpharmacological interventions targeting respiratory outcome measures in PD were included. Outcomes of interest were respiratory morbidity and mortality, respiratory muscle strength, spirometry measures, lung volumes, peak cough flow, and perception of dyspnoea. RESULTS: Nonpharmacological interventions included: functional training, generalised strength training, respiratory muscle strength training, aerobic exercise, qigong, yoga, breath stacking, incentive spirometry and singing. Methodological quality of included studies varied. Meta-analyses of nonpharmacological interventions demonstrated significant effects for inspiratory muscle strength (mean difference [MD] 19.68; confidence interval [CI] 8.49, 30.87; z = 3.45; p = 0.0006; I2  = 2%), expiratory muscle strength (MD 18.97; CI 7.79, 30.14; z = 3.33; p = 0.0009; I2  = 23%) and peak expiratory flow (MD 72.21; CI 31.19, 113.24; z = 3.45; p = 0.0006; I2  = 0%). Best-evidence synthesis identified level 1 evidence supporting nonpharmacological interventions for improving peak cough flow and perceived dyspnoea. No studies were identified reporting outcomes of respiratory rate, inspiration:expiration ratio or respiratory morbidity or mortality in PD. CONCLUSIONS: Nonpharmacological interventions improved respiratory muscle strength and peak expiratory flow in PD. Additional trials targeting respiratory dysfunction and longitudinal studies examining the relationship between respiratory dysfunction and morbidity and mortality rates in PD are required.

Impact of smoking behavior on clozapine blood levels - a systematic review and meta-analysis.

OBJECTIVE: Tobacco smoking significantly impacts clozapine blood levels and has substantial implications on individual efficacy and safety outcomes. By investigating differences in clozapine blood levels in smoking and non-smoking patients on clozapine, we aim to provide guidance for clinicians how to adjust clozapine levels for patients on clozapine who change their smoking habits. METHODS: We conducted a meta-analysis on clozapine blood levels, norclozapine levels, norclozapine/clozapine ratios, and concentration to dose (C/D) ratios in smokers and non-smokers on clozapine. Data were meta-analyzed using a random-effects model with sensitivity analyses on dose, ethnic origin, and study quality. RESULTS: Data from 23 studies were included in this meta-analysis with 21 investigating differences between clozapine blood levels of smokers and non-smokers. In total, data from 7125 samples were included for the primary outcome (clozapine blood levels in ng/ml) in this meta-analysis. A meta-analysis of all between-subject studies (N = 16) found that clozapine blood levels were significantly lower in smokers compared with non-smokers (Standard Mean Difference (SMD) -0.39, 95% confidence interval (CI) -0.55 to -0.22, P < 0.001, I2  = 80%). With regard to the secondary outcome, C/D ratios (N = 16 studies) were significantly lower in the smoker group (n = 645) compared with the non-smoker group (n = 813; SMD -0.70, 95%CI -0.84 to -0.56, P < 0.00001, I2  = 17%). CONCLUSION: Smoking behavior and any change in smoking behavior is associated with a substantial effect on clozapine blood levels. Reductions of clozapine dose of 30% are recommended when a patient on clozapine stops smoking. Reductions should be informed by clozapine steady-state trough levels and a close clinical risk-benefit evaluation.

Clinical findings, treatment and outcome of trapped neutrophil syndrome in Border Collies: 12 cases (2011-2022).

OBJECTIVES: This study aimed to evaluate clinical signs, diagnostic findings, treatment administered and short- (survival to 28 days) and long-term prognosis (survival >6 months) in dogs diagnosed with trapped neutrophil syndrome. MATERIALS AND METHODS: Medical records of 12 dogs (10 Border Collies and two Border Collie Crossbreeds) homozygous for VPS13B gene mutation causing trapped neutrophil syndrome from seven veterinary institutions between January 2011 and June 2022 were evaluated retrospectively. RESULTS: The most common clinical signs at the time of diagnosis were pyrexia, abnormal gait and gastrointestinal signs. Concurrent metaphyseal osteopathy and immune-mediated polyarthritis were common. Seven dogs had a segmented neutrophil count below, four dogs within and one dog above the analyser reference interval at presentation. Two dogs had a septic source identified and both were additionally identified to be homozygous mutant positive on DNA testing by polymerase chain reaction (PCR) for canine cyclic neutropenia. All dogs received at least one antimicrobial agent and 10 dogs received treatment with prednisone or prednisolone (median starting dose 1 mg/kg/day; range 0.5 to 2.5 mg/kg/day). Nine dogs were alive at 28 days and six dogs were alive at 6 months post-diagnosis. CLINICAL SIGNIFICANCE: Trapped neutrophil syndrome should be suspected in young Border Collies with pyrexia, lameness and gastrointestinal signs. Neutropenia may not always be present and long-term survival is possible. A septic focus was not commonly identified in our population; however, our results suggest that if identified, testing for concurrent canine cyclic neutropenia should be considered.

Large vessel calcification in Takayasu arteritis.

We report the novel case of a young woman with Takayasu arteritis, with extensive large vessel disease. The case demonstrates that while mechanisms of vascular calcification are poorly understood, inflammation per se might be sufficient to mediate increased mineral stress leading to vessel calcification, even in the absence of renal impairment.

Prediction of pre-eclampsia in early pregnancy by estimating the spot urinary albumin: creatinine ratio using high-performance liquid chromatography.

OBJECTIVE: To establish whether a spot urinary albumin: creatinine ratio (ACR) measured before 20 weeks of gestation can predict subsequent pre-eclampsia when urinary albumin is measured by high-performance liquid chromatography (HPLC). DESIGN: Prospective exploratory study. SETTING: Antenatal clinic in a tertiary teaching hospital, Victoria, Australia. POPULATION: A cohort of 265 women with a singleton pregnancy, normal renal function, and no evident proteinuria, attending antenatal clinics between 12 and 20 weeks of gestation. METHODS: The ACR was determined from a mid-stream urine (MSU) sample taken between 17 and 20 weeks of gestation. Intact urinary albumin was determined by HPLC; creatinine was measured by modified Jaffe's method. OUTCOME MEASURES: Pre-eclampsia (primary); gestational hypertension, small for gestational age (SGA), gestational diabetes mellitus, gestational age at delivery, and prematurity (secondary). RESULTS: The median ACR was 28 mg/mmol (IQR 16-46 mg/mmol). Women who subsequently developed pre-eclampsia had a significantly higher ACR (median 50 mg/mmol; IQR 33-90 mg/mmol) compared with women suffering from gestational hypertension (median 27 mg/mmol; IQR 8-35 mg/mmol), and compared with unaffected women (median 28 mg/mmol; IQR 16-46 mg/mmol). Mothers of SGA infants also had a significantly higher median ACR. By ROC analysis, the optimum ACR to predict pre-eclampsia was 35.5 mg/mmol: the relative risk of developing pre-eclampsia in women with a urinary ACR ≥ 35.5 mg/mmol was 7.8 times more than in those with a urinary ACR < 35.5 mg/mmol. CONCLUSIONS: When urinary albumin is measured by HPLC, spot urinary ACR values are higher in early uncomplicated pregnancy compared with previously reported conventional methods. When measured early in the second trimester, an ACR ≥ 35.5 mg/mmol predicted pre-eclampsia well before the onset of clinical manifestations.

An observational study of the effectiveness of darbepoetin alpha administered in dialysis patients once every 2 weeks for 12 months.

AIMS: Erythropoiesis-stimulating agents (ESAs) are recommended for managing renal anemia. ALTERNATE is an observational study in European and Australian dialysis patients evaluating darbepoetin a (DA) once every 2 weeks (Q2W) in clinical practice. METHODS: Adult dialysis patients initiating treatment with DA Q2W were eligible regardless of previous/current ESA use. Data were collected 6 months before and 12 months after Q2W initiation. The primary endpoint was hemoglobin (Hb) concentration 12 months after initiation. RESULTS: A total of 6,112 patients were enrolled; 6,104 were eligible (87% hemodialysis, 12% peritoneal dialysis). Before initiation, 77.3%, 8.8%, and 7.8% of patients were receiving DA, epoetin beta, and epoetin alpha, respectively; 6% were ESA naïve. Mean (95% CI) Hb (g/dl) was 11.68 (11.63-11.72) 6 months before initiation, 12.00 (11.97-12.04) at initiation, and 11.62 (11.58-11.66) 12 months after initiation. Geometric mean (95% CI) weekly ESA dose (µg/wk) was 27.27 (26.62-27.93) immediately before initiation, 23.69 (23.28 - 24.10) at initiation, and 26.80 (26.12-27.49) 12 months after initiation. At month 12, 77.3% of patients were receiving DA Q2W. CONCLUSIONS: This large observational study demonstrates that Hb concentrations can be effectively maintained over 12 months in a general dialysis population with DA Q2W without an increase in ESA dose.

Increased O-GlcNAcylation rapidly decreases GABAAR currents in hippocampus but depresses neuronal output.

O-GlcNAcylation, a post-translational modification involving O-linkage of ß-N-acetylglucosamine to Ser/Thr residues on target proteins, is increasingly recognized as a critical regulator of synaptic function. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. An acute increase in O-GlcNAcylation can affect neuronal communication by inducing long-term depression (LTD) of excitatory transmission at hippocampal CA3-CA1 synapses, as well as suppressing hyperexcitable circuits in vitro and in vivo. Despite these findings, to date, no studies have directly examined how O-GlcNAcylation modulates the efficacy of inhibitory neurotransmission. Here we show an acute increase in O-GlcNAc dampens GABAergic currents onto principal cells in rodent hippocampus likely through a postsynaptic mechanism, and has a variable effect on the excitation/inhibition balance. The overall effect of increased O-GlcNAc is reduced synaptically-driven spike probability via synaptic depression and decreased intrinsic excitability. Our results position O-GlcNAcylation as a novel regulator of the overall excitation/inhibition balance and neuronal output.

The diagnosis of gestational diabetes mellitus (GDM) using a 75 g oral glucose tolerance test: A prospective observational study.

AIMS: Screening for Gestational Diabetes Mellitus (GDM) is controversial. This prospectivestudy compared different sets of diagnostic cut-off points for plasma glucose measurements following a 75 g Oral Glucose Tolerance Test (OGTT). METHODS: Women who had maternal risk factors for GDM were recruited at their convenience attheir first prenatal visit and consented to a one-step OGTT at 26-28 weeks gestation.All women fulfilling the World Health Organization (WHO) 2013 diagnostic criteriareceived standard care for GDM. RESULTS: Of the 202 women, 139 (69%) had one risk factor for GDM and 63 (31%) had > 1.Using the WHO criteria, 53% (n = 108) had GDM compared with 35% (n = 71) usingCanadian criteria and 18% (n=36) using National Institute for Health Care Excellencecriteria (NICE) criteria (both p<0.001). Of the 108 women, 50% (n = 54) requiredpharmacological treatment to control hyperglycaemia. If the Canadian criteria wereapplied, 11/54 (20.4%) women would not have received hypoglycaemics. If the NICEcriteria were applied, 36/54 (66.7%) women would not have received hypoglycaemics.Maternal insulin, HOMA-IR and C-peptide measured at the time of the OGTT showed evidence of increased insulin resistance in women who had GDM based on the WHOcriteria but who had a normal OGTT based on the Canadian or NICE criteria. CONCLUSIONS: Under stringent research conditions, our study suggeststhat the Canadian and, in particular, the NICE criteria are not identifying women who may benefit fromimproved glycaemic control. These findings support the need for the planned review of the NICE guidelines on GDM in 2020.

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease.

In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment 'successes' was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment 'successes', molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in 'success' rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the 'success' rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.

Hippocampal interneurons express a novel form of synaptic plasticity.

Individual GABAergic interneurons in hippocampus can powerfully inhibit more than a thousand excitatory pyramidal neurons. Therefore, control of interneuron excitability provides control over hippocampal networks. We have identified a novel mechanism in hippocampus that weakens excitatory synapses onto GABAergic interneurons. Following stimulation that elicits long-term potentiation at neighboring synapses onto excitatory cells, excitatory synapses onto inhibitory interneurons undergo a long-term synaptic depression (interneuron LTD; iLTD). Unlike most other forms of hippocampal synaptic plasticity, iLTD is not synapse specific: stimulation of an afferent pathway triggers depression not only of activated synapses but also of inactive excitatory synapses onto the same interneuron. These results suggest that high frequency afferent activity increases hippocampal excitability through a dual mechanism, simultaneously potentiating synapses onto excitatory neurons and depressing synapses onto inhibitory neurons.

Transdermal absorption of the herbicide 2,4-dichlorophenoxyacetic acid is enhanced by both ethanol consumption and sunscreen application.

Xenobiotics absorption is a health concern and skin is a major exposure site for many of these chemicals. Both alcohol consumption and topical sunscreen application act as transdermal penetration enhancers for model xenobiotics. The effect of combining these two treatments on transdermal absorption of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was therefore examined. Skin from rats ingesting low (1.5 g/kg) medium (4.3 g/kg) or high (6 g/kg) ethanol doses or saline control was treated with a commercially available sunscreen containing titanium dioxide and octyl methoxycinnimate and transdermal absorption of 2,4-D was monitored. Ethanol increased penetration by a factor of 1.9, 2.0 and 2.5 for animals treated with 1.5, 4.3 and 6 g/kg respectively, demonstrating an ethanol-induced dose response. Sunscreen application to skin from ethanol gavaged rats caused 2,4-D absorption above that induced by ethanol alone by an additional factor of 1.3, 2.1 and 2.9 for 1.5, 4.3 and 6 g/kg respectively. Comparing 2,4-D transdermal absorption after exposure to both ethanol and sunscreen with a theoretical value (sum of penetration after ethanol or sunscreen treatment) demonstrates that these two treatments enhance additively at the higher doses tested. Results of this study emphasize the importance of limiting excessive alcohol consumption in individuals with potential herbicide exposure rather than discouraging the use of sunscreens, since the consequences of UV-induced skin cancer are far more series than the risks that would be associated with observed increases in chemical exposure.

Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors.

Serotonin [5-hydroxytryptamine (5-HT)] 5-HT(2A) and 5-HT(2C) receptors (5-HT(2A)Rs and 5-HT(2C)Rs), which innervate the dopamine mesoaccumbens pathway, may play an important role in the behavioral effects of cocaine. To test this hypothesis, the present study measured cocaine-evoked locomotor activity after bilateral microinjection of selective 5-HT(2A)R and 5-HT(2C)R antagonists into the ventral tegmental area (VTA) or the nucleus accumbens (NAc) shell. Locomotor activity was measured after intracranial microinjection of saline (0.2 microl/side), the selective 5-HT(2A)R antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol (M100907) (0.1 or 0.3 microg. 0.2 microl(-1). side(-1)), or the selective 5-HT(2C)R antagonist 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfon-amido)phenyl-5-oxopentyl)]-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (RS 102221) (0.05-0.5 microg. 0.2 microl(-1). side(-1)) followed by an injection of saline (1 ml/kg, i.p.) or cocaine (10 mg/kg, i.p.). Microinjection of M100907 (0.1-0.3 microg/side) into the VTA or RS 102221 (0.15-0.5 microg/side) into the NAc shell attenuated cocaine-induced hyperactivity in a dose-related manner. However, hyperactivity evoked by cocaine was not altered by microinjection of RS 102221 into the VTA or M100907 into the NAc shell. No changes in basal activity were observed after microinjection of M100907 or RS 102221 into either brain region. These findings are the first to demonstrate that the behavioral effects of cocaine are generated in part by activation of 5-HT(2A)Rs in the VTA and by activation of 5-HT(2C)Rs in the NAc shell. The selective regulation of the mesoaccumbens circuit by 5-HT(2A)Rs and 5-HT(2C)Rs implicates these 5-HT receptors as important in the behavioral outcomes of systemic cocaine administration.

Treatment of small cell lung cancer with VP-16, vincristine, doxorubicin (Adriamycin), cyclophosphamide (EVAC), and high-dose chest radiotherapy.

Seventy-one previously untreated patients with small cell lung cancer (SCLC) received a combination of VP-16, vincristine, doxorubicin (Adriamycin), and cyclophosphamide (EVAC) repeated every three weeks. Limited-disease (LD) patients and extensive-disease (ED) patients achieving a complete response (CR) or partial response (PR) after four to six cycles of EVAC received 4,000 rads over four weeks whole-brain radiotherapy (RT) and 5,000 rads over five weeks RT to the original pulmonary primary and mediastinum. ED patients with persisting disease outside the chest after six cycles of EVAC continued chemotherapy and did not receive RT. After RT was completed, EVAC was continued for a total treatment duration of 24 months. Of 65 patients evaluable for response 76% (25 of 33) of LD patients and 34% (11 of 32) of ED patients achieved a CR prior to RT; two additional ED patients achieved a CR after RT. Median survival for all 71 patients was 48 weeks (range, one to 207 weeks); median survival for 33 LD patients was 92 weeks and for 38 ED patients it was 36 weeks. Nine of 25 LD patients and 10 of 13 ED patients have relapsed from CR. The EVAC-RT protocol is promising in view of the high CR rate and long remission duration achieved, especially among patients with LD.

Modulation of the protein kinase activity of mTOR.

mTOR is a founding member of a family of protein kinases having catalytic domains homologous to those in phosphatidylinositol 3-OH kinase. mTOR participates in the control by insulin of the phosphorylation of lipin, which is required for adipocyte differentiation, and the two translational regulators, p70S6K and PHAS-I. The phosphorylation of mTOR, itself, is stimulated by insulin in Ser2448, a site that is also phosphorylated by protein kinase B (PKB) in vitro and in response to activation of PKB activity in vivo. Ser2448 is located in a short stretch of amino acids not found in the two TOR proteins in yeast. A mutant mTOR lacking this stretch exhibited increased activity, and binding of the antibody, mTAb-1, to this region markedly increased mTOR activity. In contrast, rapamycin-FKBP12 inhibited mTOR activity towards both PHAS-I and p70S6K, although this complex inhibited the phosphorylation of some sites more than that of others. Mutating Ser2035 to Ile in the FKBP12-rapamycin binding domain rendered mTOR resistant to inhibition by rapamycin. Unexpectedly, this mutation markedly decreased the ability of mTOR to phosphorylate certain sites in both PHAS-I and p70S6K. The results support the hypotheses that rapamycin disrupts substrate recognition instead of directly inhibiting phosphotransferase activity and that mTOR activity in cells is controlled by the phosphorylation of an inhibitory regulatory domain containing the mTAb-1 epitope.

Cross-tolerance and mu agonist efficacy in pigeons treated with LAAM or buprenorphine.

The mechanism responsible for decreased opioid use during opioid substitution therapy is not fully understood. To examine whether l-alpha-acetylmethadol (LAAM) or buprenorphine attenuate behavioral effects of opioids through cross-tolerance, discriminative stimulus effects of high and low efficacy mu agonists were examined following 3- or 7-day treatment with LAAM or buprenorphine in pigeons discriminating between saline and heroin or between saline and buprenorphine, respectively. Heroin, buprenorphine and nalbuphine occasioned high levels of drug-appropriate responding in both groups; kappa opioids and non-opioids occasioned predominantly saline-appropriate responding. Administration of LAAM (3.2 mg/kg) or buprenorphine (3.2 mg/kg) occasioned predominantly heroin- or buprenorphine-appropriate responding, respectively. After discontinuation of LAAM treatment, the potency in occasioning heroin-key responding was markedly decreased for nalbuphine, slightly decreased for buprenorphine, and unchanged for heroin. Following discontinuation of buprenorphine treatment, the potency in occasioning buprenorphine-key responding was decreased for nalbuphine and unchanged for buprenorphine and heroin. Thus, greater cross-tolerance developed from LAAM and buprenorphine to low efficacy mu agonists as compared to a higher efficacy agonist. Failure of LAAM and buprenorphine treatment to modify the effects of heroin, under conditions that attenuate the effects of lower efficacy mu opioids, provides a possible rationale for why heroin abuse persists in some patients receiving large doses of agonists in substitution therapy.