Chronic Dosing Schedule Research Articles

Amphetamine-induced alteration to gaze parameters: A novel conceptual pathway and implications for naturalistic behavior.

Amphetamine produces a multiplicity of well-documented end-order biochemical, pharmacological and biobehavioural effects. Mechanistically, amphetamine downregulates presynaptic and postsynaptic striatal monoamine (primarily dopaminergic) systems, producing alterations to key brain regions which manifest as stereotyped ridged behaviour which occurs under both acute and chronic dosing schedules and persists beyond detoxification. Despite evidence of amphetamine-induced visual attentional dysfunction, no conceptual synthesis has yet captured how characteristic pharmaco-behavioural processes are critically implicated via these pathways, nor described the potential implications for safety-sensitive behaviours. Drawing on known pathomechanisms, we propose a cross-disciplinary, novel conceptual functional system framework for delineating the biobehavioural consequences of amphetamine use on visual attentional capacity and discuss the implications for functional and behavioural outcomes. Specifically, we highlight the manifest implications for behaviours that are conceptually driven and highly dependent on visual information processing for timely execution of visually-guided movements. Following this, we highlight the potential impact on safety-sensitive, but common behaviours, such as driving a motor vehicle. The close pathophysiological relationship between oculomotor control and higher-order cognitive processes further suggests that dynamic measurement of movement related to the motion of the eye (gaze behaviour) may be a simple, effective and direct measure of behavioural performance capabilities in naturalistic settings. Consequently, we discuss the potential efficacy of ocular monitoring for the detection and monitoring of driver states for this drug user group, and potential wider application. Significance statement: We propose a novel biochemical-physiological-behavioural pathway which delineates how amphetamine use critically alters oculomotor function, visual-attentional performance and information processing capabilities. Given the manifest implications for behaviours that are conceptually driven and highly dependent on these processes, we recommend oculography as a novel means of detecting and monitoring gaze behaviours during naturalistic tasks such as driving. Real-word examination of gaze behaviour therefore present as an effective means to detect driver impairment and prevent performance degradation due to these drugs.

How preclinical studies have influenced novel psychoactive substance legislation in the UK and Europe.

Novel psychoactive substances (NPS) are new drugs of abuse. Over the last 10 years 50-100 new NPS have been detected for the first time each year. This has led to numerous deaths and challenges to healthcare providers and law-makers worldwide. We review preclinical studies of NPS and discuss how these studies have influenced legislative decisions. We focus on the UK legal system but include experiences from Europe. We reviewed manuscripts from 2008-2019 and have summarised the in vitro and in vivo data on NPS, highlighting how these studies define pharmacological mechanisms and how they might predict harm in humans. We found that only a small percentage of NPS have been examined in preclinical studies. Most preclinical studies of NPS focus on basic pharmacological mechanisms (46% of studies reviewed) and/or addictive liability (32%) rather than toxicity and harm (24%). Very few preclinical studies into NPS include data from chronic dosing schedules (9%) or female rodents (4%). We conclude that preclinical studies can predict harm to humans, but most of the predictions are based on basic pharmacology rather than demonstrated toxicity. Some of these studies have been used to make changes to the law in the UK and Europe and perhaps, because of the paucity of toxicology data, most NPS have been placed in the highly dangerous schedule 1 or Class A category in the UK. We suggest that in silico studies and high throughput toxicology screens might be the most economical way forward to rapidly screen the health harms of NPS.

Repurposing ospemifene for potentiating an antigen-specific immune response

Ospemifene, an estrogen receptor agonist/antagonist approved for the treatment of dyspareunia and vaginal dryness in postmenopausal women, has potential new indications as an immune modulator. The overall objective of the present series of preclinical studies was to evaluate the immunomodulatory activity of ospemifene in combination with a peptide cancer vaccine. Immune regulating effects, mechanism of action and structure activity relationships of ospemifene and related compounds were evaluated by examining expression of T-cell activating cytokines in vitro, and antigen-specific immune response and cytotoxic T-lymphocyte activity in vivo. The effects of ospemifene (OSP) on the immune response to a peptide cancer vaccine (PV) were evaluated after chronic [control (n = 22); OSP 50 mg/kg (n = 16); PV (n = 6); OSP+PV (n = 11)], intermittent [control (n = 10); OSP 10 and 50 mg/kg (n = 11); PV (n = 11); combination treatment (n = 11 each dose)] and pretreatment [control; OSP 100 mg/kg; PV 100 μg; combination treatment (n = 8 all groups)] ospemifene oral dosing schedules in a total of 317 mixed-sex tumor-bearing and nontumor-bearing mice. The results showed that ospemifene induced expression of the key TH1 cytokines interferon gamma and interleukin-2 in vitro, which may be mediated by stimulating T-cells through phosphoinositide 3-kinase and calmodulin signaling pathways. In combination with an antigen-specific peptide cancer vaccine, ospemifene increased antigen-specific immune response and increased cytotoxic T-lymphocyte activity in tumor-bearing and nontumor-bearing mice. The pretreatment, intermittent, and chronic dosing schedules of ospemifene activate naive T-cells, modulate antigen-induced tolerance and reduce tumor-associated, pro-inflammatory cytokines, respectively. Taken together, ospemifene's dose response and schedule-dependent immune modulating activity offers a method of tailoring and augmenting the efficacy of previously failed antigen-specific cancer vaccines for a wide range of malignancies.

Pro‐osteolytic effects of chronic morphine administration in a model of breast cancer‐induced bone pain.

Many common cancers have a high propensity for bone metastasis; for breast cancer, bone metastasis affects 70% of advanced patients and is the most common site for secondary tumor relapse. Tumor manifestation disrupts bone homeostasis and results in debilitating chronic skeletal pain that decreases patient functional status, quality of life and survival. Morphine remains the golden standard for managing cancer‐induced bone pain; however, opioids including morphine are associated with a host of side effects that complicate chronic dosing schedules. Furthermore, it has been posited that morphine may accelerate bone wasting in patients; in models of secondary bone metastasis, morphine exacerbates fracture rate, markers of osteolysis, and pain behaviors.We sought to determine whether morphine exacerbates bone loss in the 66.1‐Balb/C model of breast cancer‐induced bone metastasis (BCBM). Sham and tumor‐inoculated animals received a constant morphine infusion for 7 days (20 mg/kg/day). Morphine produced initial analgesia but failed to manage behaviors indicative of cancer‐induced bone pain over time; additionally, morphine treatment increased TRACP 5b in sera and RANKL in femur extrudate, suggesting that morphine enhances osteolysis in BCBM. In vitro studies evaluated the ability of morphine to induce osteoclastogenesis in the presence of permissive levels of RANKL. Morphine did not appear to affect tumor burden in vivo or in vitro viability of tumor cells. These data suggest that morphine worsens bone loss in the 66.1‐Balb/C model and may act directly on osteoclast cells; however, the exact mechanism of morphine‐induced bone loss is unknown and remains a barrier to improving pain relief in suffering BCBM patients.

3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors

Nicotine (NIC), the main psychostimulant compound of smoked tobacco, exerts its effects through activation of central nicotinic acetylcholine receptors (nAChR), which become up-regulated after chronic administration. Recent work has demonstrated that the recreational drug 3,4-methylenedioxy-methamphetamine (MDMA) has affinity for nAChR and also induces up-regulation of nAChR in PC 12 cells. Tobacco and MDMA are often consumed together. In the present work we studied the in vivo effect of a classic chronic dosing schedule of MDMA in rats, alone or combined with a chronic schedule of NIC, on the density of nAChR and on serotonin reuptake transporters. MDMA induced significant decreases in [3H]paroxetine binding in the cortex and hippocampus measured 24h after the last dose and these decreases were not modified by the association with NIC. In the prefrontal cortex, NIC and MDMA each induced significant increases in [3H]epibatidine binding (29.5 and 34.6%, respectively) with respect to saline-treated rats, and these increases were significantly potentiated (up to 72.1%) when the two drugs were associated. Also in this area, [3H]methyllycaconitine binding was increased a 42.1% with NIC+MDMA but not when they were given alone. In the hippocampus, MDMA potentiated the α7 regulatory effects of NIC (raising a 25.5% increase to 52.5%) but alone was devoid of effect. MDMA had no effect on heteromeric nAChR in striatum and a coronal section of the midbrain containing superior colliculi, geniculate nuclei, substantia nigra and ventral tegmental area. Specific immunoprecipitation of solubilised receptors suggests that the up-regulated heteromeric nAChRs contain α4 and β2 subunits. Western blots with specific α4 and α7 antibodies showed no significant differences between the groups, indicating that, as reported for nicotine, up-regulation caused by MDMA is due to post-translational events rather than increased receptor synthesis.

Phase 2 study of granulocyte-macrophage colony-stimulating factor plus thalidomide in patients with hormone-naïve adenocarcinoma of the prostate

Objective To assess the efficacy of granulocyte macrophage colony-stimulating factor (GM-CSF) in combination with thalidomide on prostate-specific antigen (PSA) reduction in hormone-naïve prostate carcinoma (HNPC) patients with rising PSA levels after definitive local treatment. Materials and methods HNPC patients ( n = 21) with evidence of progression demonstrated by 3 consecutive rises in PSA and no evidence of radiographic involvement were treated on a chronic dosing schedule with GM-CSF. Patients received 250 μg/m 2 (maximum 500 μg) 3 times a wk by subcutaneous injection, with injections at least 24 h apart. Thalidomide administration began concurrently with an initial dose of 100 mg daily for 7 consecutive days. During wk 2 to 4, the dose was escalated every 7 d by 100 mg per individual tolerance to a maximum of 400 mg. The maximum tolerated dose of thalidomide was continued without interruption. PSA, testosterone, and routine laboratory parameters were measured every 6 wk. Results One patient was not evaluable because of noncompliance. For the 20 evaluable patients, baseline PSA levels ranged from 1.3 to 61.0 ng/ml. Nineteen patients left the study at 3.0 to 33.3 mo, secondary to individual tolerance, progressive disease, or development of a second primary tumor. One patient continues to receive therapy at 33.8 mo. Two patients did not respond to the therapy. For the 18 patients who did respond, the median reduction in PSA level was 59% (range 26%–89%), and the median duration of response was 11 mo (range 4.5–36). Grades 1–2 toxicity included peripheral neuropathy, fatigue, skin rash, and constipation. One patient had deep-vein thrombosis/pulmonary embolism. Conclusions GM-CSF plus thalidomide can be administered successfully with encouraging antitumor activity and reversible toxicity. This may represent an alternative to hormonal therapy.

Augmentation Treatment of Psychotherapy for Anxiety Disorders with D‐Cycloserine

Anxiety disorders are among the most common mental disorders. One of the most effective strategies to treat anxiety disorders is exposure therapy with or without cognitive intervention. Fear reduction in exposure therapy is similar to extinction learning. Preclinical studies suggest that extinction learning can be blocked by antagonists at the glutamatergic N-methyl-D-aspartate (NMDA) receptor, and facilitated with D-cycloserine (DCS), a partial agonist at the glycine recognition site of the NMDA receptor in the amygdala. DCS is an established antibiotic drug for the chronic treatment of tuberculosis in humans, but has only recently been investigated as an augmentation therapy for psychological treatment procedures. The review of the literature provides preliminary support for the use of acute dosing of DCS as an adjunctive intervention to exposure therapy for anxiety disorders, including specific phobia and social anxiety disorder. Negative results have recently been reported in the treatment of subclinical fears of animals. These studies suggest that DCS needs to be administered on an acute rather than a chronic dosing schedule, include sufficient time for memory consolidation, and be administered together with psychological treatment that leaves sufficient room for further improvement. It remains to be seen whether these highly promising findings represent reliable pharmacological strategies to enhance exposure therapy of anxiety disorders.

An increase in sensitivity of rat cingulate cortical neurones to substance P occurs following withdrawal of chronic administration of antidepressant drugs.

The sensitivity of neurones in the cingulate cortex of the rat to iontophoretically applied substance P (SP) was tested one hour after a single dose of various antidepressant drugs and also 1 day following the termination of a chronic dosing schedule (14 once daily injections) of the same agents. One hour after a single injection of desipramine (DMI), chlorimipramine (CMI), trimipramine (TMI) or zimelidine ( ZIM ) (all at 10 mg kg-1 i.p.) there was no change in the mean size of excitatory responses to SP compared to those before the injection. There was a tendency towards a decrease in the TMI group. One day following the last of 14 consecutive daily injections (10 mg kg-1 i.p.) of the above agents there was a significant increase in the size of excitatory responses to SP compared to those in rats receiving daily saline injections. However, 14 days of treatment with DMI did not alter the responses to L-glutamate. Similar chronic dosing schedules with either diazepam (5 mg kg-1) or fluphenazine (5 mg kg-1) did not affect the responses to SP. Thus chronic but not acute administration of antidepressant drugs results in an increase in the sensitivity of neurones, in the cingulate cortex of the rat, to SP.