Acetylcholinesterase inhibition dose–response modeling for chlorpyrifos and chlorpyrifos-oxon

This paper evaluates new data for cholinesterase inhibition with chlorpyrifos (CPF). Marty et al. (2012) recently conducted a CPF cholinesterase inhibition study in rats that included testing of males and females, dosing by gavage or diet, administration in corn oil or milk, and with pups and adults. Additionally, the study included cholinesterase inhibition testing for CPF-oxon, the active moiety that inhibits cholinesterase. The study included 5–6 dose groups with eight animals/sex/group for most of the tests. This paper provides a benchmark dose (BMD) analysis of the data from Marty et al. (2012), including a BMD meta-analysis that includes CPF cholinesterase inhibition data from different assays within the Marty et al. (2012) study and, in one case, from another study. From the meta-analysis, the recommended BMD₁₀s, based on brain acetylcholinesterase inhibition, are 1.7 mg/kg/day (BMDL₁₀ = 1.3 mg/kg/day) for acute doses to children and adults, and 0.67 mg/kg/day (BMDL₁₀ = 0.53 mg/kg/day) for repeat doses to children and adults. At the dose levels considered in this analysis, there was no evidence of a difference in responses between males and females, corn oil versus milk administration, or pups versus adults. The data on pups versus adults show that an extra safety factor to protect the young is not needed for CPF. CPF data from the literature suggest that brain cholinesterase inhibition is the most appropriate metric for cholinesterase inhibition risk assessment.     

Test and treat or treat and test in reflux disease?

The role of diagnostic testing in reflux disease is in evolution. There is little question that patients with dysphagia, bleeding or other 'alarm' symptoms, should undergo early endoscopy. A substantial proportion of patients presenting with reflux symptoms have endoscopy negative reflux disease. pH testing is both inconvenient and lacks the sensitivity and specificity required for a 'gold standard'. Empirical trials of therapy using proton pump inhibitors have shown that a trial of treatment may be the most accurate way of diagnosing gastro-oesophageal reflux disease (GERD) and may the optimal strategy from a cost-effectiveness standpoint. On the other hand, the increasing rate of oesophageal adenocarcinoma has raised questions about the possible value of screening endoscopy to determine if Barrett's oesophagus is present. The role of endoscopic testing in the average patient is therefore shifting from a diagnostic modality to one that helps manage risk by identifying Barrett's oesophagus.     

Does pharmacotherapy for preterm labor sensitize the developing brain to environmental neurotoxicants? Cellular and synaptic effects of sequential exposure to terbutaline and chlorpyrifos in neonatal rats

It is increasingly clear that environmental toxicants target specific human subpopulations. In the current study, we examined the effects of prior developmental exposure to a beta(2)-adrenoceptor agonist used to arrest preterm labor, terbutaline, on the subsequent effects of exposure to the organophosphate insecticide, chlorpyrifos (CPF). Neonatal rats were given terbutaline on postnatal day (PN) 2-5, followed by CPF on PN11-14. Although neither treatment affected growth or viability, each elicited alterations in indices of brain cell differentiation and cholinergic innervation in the immediate posttreatment period (PN15), persisting into adulthood (PN60). Biomarkers of brain cell number (DNA concentration and content), cell size (protein/DNA ratio) and neuritic projections (membrane/total protein) were affected by either agent alone, with patterns consistent with neuronal and neuritic damage accompanied by reactive gliosis. The combined exposure augmented these effects by both additive and synergistic mechanisms. Similarly, choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was affected only by combined exposure to both terbutaline and CPF. Indices of cholinergic synaptic activity [hemicholinium-3 and m(2)-muscarinic acetylcholine receptor binding] showed impairment after exposure to either terbutaline or CPF but the effects were more severe when the treatments were combined. These findings suggest that terbutaline, like CPF, is a developmental neurotoxicant, and that its use in the therapy of preterm labor may create a subpopulation that is sensitized to the adverse neural effects of a subsequent exposure to organophosphate insecticides.     

Gestational exposure to the organophosphate chlorpyrifos alters social–emotional behaviour and impairs responsiveness to the serotonin transporter inhibitor fluvoxamine in mice

Background

The organophosphate chlorpyrifos (CPF) is a pesticide largely used worldwide. Studies from animal models indicate that CPF exposure during development at low doses can target different neurotransmitter systems in the absence of overt cholinergic effects.

Methods

Late gestational exposure (gestational days 14–17) to CPF at the dose of 6 mg/kg was evaluated in CD-1 mice at adulthood. Neurobehavioural effects likely involving serotonin (5-hydroxytryptamine, 5HT) transmission were assessed both in males and females, through the light–dark exploration test to assess CPF effects on anxiety profiles and the forced swimming test to evaluate the response to the 5HT transporter (5HTT) inhibitor fluvoxamine (30 mg/kg). In females only, we evaluated the effects of gestational exposure to CPF on maternal aggression, under basal condition or after injection of fluvoxamine.

Results

Gestational CPF exposure increased anxiety levels only in female mice, as shown by the augmented thigmotaxis behaviour and the lower latency to enter in the dark compartment. In the forced swimming test, no differences between CPF and control mice were found when assessed under basal condition (saline administration), but both male and female CPF mice missed to show the typical behavioural effects of the 5HTT inhibitor fluvoxamine. During maternal aggression, CPF females showed lower propensity to and intensity of aggressive behaviour, together with mild decreased responsiveness to fluvoxamine administration.

Conclusions

Overall, the present results confirm a specific and sex-dependent vulnerability of affective/emotional domains to developmental CPF exposure. Furthermore, data provide clear indication on the disrupting effects of prenatal CPF on serotoninergic transmission.     

Cilostazol and primary-PCI: mirage or good alternative?

Oral anti-platelet agents targeting the platelet P2Y12 receptor are an integral component of treating patients undergoing percutaneous coronary interventions. Advancements in the design of stents and catheters are pushing the technique towards treatment of high risk lesions whose failure would expose patients to catastrophic events. Success of these complex procedures largely lays on efficacy of anti-platelet drugs and the limitation of stent restenosis and/or thrombosis. Clopidogrel has been the most commonly used agent in this respect worldwide. However, there are certain shortcomings of clopidogrel, the most important of which is the wide response variability of platelet inhibition. Thus, clinicians are facing challenges in treating patients where high inhibition of platelets is necessary and the response to clopidogrel may be insufficient. In the last few years, cilostazol, a phosphodiesterase (PDE) 3 inhibitor, has been tested in the setting of acute coronary syndromes: it exerts not only anti-platelet actions, but also pleiotropic effects, including inhibition on neointimal hyperplasia, therefore preventing both stent restenosis and thrombosis. Therefore, cilostazol may be considered, on top of our current anti-platelet therapy, as a potential candidate to achieve optimal platelet inhibition especially in patients undergoing primary-PCI (p-PCI) or high risk procedures. This review will focus on the pharmacological characteristics of cilostazol and the initial evidences that support the use of this drug in the setting of p-PCI.     

Erlotinib and pantoprazole: a relevant interaction or not?

AIMS

There is increasing evidence that erlotinib exposure correlates well with treatment outcome. In this report we present a case of therapeutic drug monitoring of erlotinib in a patient with a gastric ulcer, treated with the proton pump inhibitor pantoprazole. This agent may cause an unwanted, but not always unavoidable, interaction since absorption of erlotinib is pH dependent.

METHODS

Erlotinib trough concentrations were monitored in a patient during treatment with orally and intravenously administered pantoprazole.

RESULTS

Erlotinib trough concentrations were diminished during high dose intravenously administered pantoprazole, but returned to normal when the dose was reduced and pantoprazole was administered orally.

CONCLUSIONS

More studies are needed to assess the dose dependency of the interaction between pantoprazole and erlotinib. Furthermore, we advise to monitor closely erlotinib plasma concentrations and adjust the erlotinib dose accordingly when a clinically relevant interaction is suspected and no proper dosing guidelines are available.     

Hormone therapy and Alzheimer's disease: benefit or harm?

Alzheimer's disease (AD) is the most common cause of dementia. After menopause, circulating levels of oestrogens decline markedly and oestrogen influences several brain processes predicted to modify AD risk. For example, oestrogen reduces the formation of beta-amyloid, a biochemical hallmark of AD. Oestrogen effects on oxidative stress and some effects on inflammation and the cerebral vasculature might also be expected to ameliorate risk. However, AD pathogenesis is incompletely understood and other oestrogen actions could be deleterious. Limited clinical trial evidence suggests that oestrogen therapy, begun after the onset of AD symptoms, is without substantial benefit or harm. Observational studies have associated oestrogen-containing hormone therapy with reduced AD risk. However, in the Women's Health Initiative Memory Study - a randomised, placebo-controlled trial of women 65 - 79 years of age - oral oestrogen plus progestin doubled the rate of dementia, with heightened risk appearing soon after treatment was initiated. Based on current evidence, hormone therapy is thus not indicated for the prevention of AD. Discrepancies between observational studies and the Women's Health Initiative clinical trial may reflect biases and unrecognised confounding factors in observational reports. Other explanations for divergent findings should be considered in future research, including effects of unopposed oestrogen or different hormone therapy preparations and the intriguing theoretical possibility that effects of hormone therapy on AD risk may be modified by the timing of use (e.g., initiation during the menopausal transition or early postmenopause versus initiation during the late postmenopause).     

Macrophages and depression – A misalliance or well-arranged marriage?

Depression is a severe medical condition with multiple manifestations and diverse, largely unknown etiologies. The immune system, particularly macrophages, plays an important role in the pathology of the illness. Macrophages represent a heterogeneous population of immune cells that is dispersed throughout the body. The central nervous system is populated by several types of macrophages, including microglia, perivascular cells, meningeal and choroid plexus macrophages and pericytes. These cells occupy different brain compartments and have various functions. Under basal conditions, brain macrophages support the proper function of neural cells, organize and preserve the neuronal network and maintain homeostasis. As cells of the innate immune system, they recognize and react to any disturbances in homeostasis, eliminating pathogens or damaged cells, terminating inflammation and proceeding to initiate tissue reconstruction. Disturbances in these processes result in diverse pathologies. In particular, tissue stress or malfunction, both in the brain and in the periphery, produce sustained inflammatory states, which may cause depression. Excessive release of proinflammatory mediators is responsible for alterations of neurotransmitter systems and the occurrence of depressive symptoms. Almost all antidepressive drugs target monoamine or serotonin neurotransmission and also have anti-inflammatory or immunosuppressive properties. In addition, non-pharmacological treatments, such as electroconvulsive shock, can also exert anti-inflammatory effects. Recent studies have shown that antidepressive therapies can affect the functional properties of peripheral and brain macrophages and skew them toward the anti-inflammatory M2 phenotype. Because macrophages can affect outcome of inflammatory diseases, alleviate sickness behavior and improve cognitive function, it is possible that the effects of antidepressive treatments may be, at least in part, mediated by changes in macrophage activity.     

Crohn's disease and celiac disease: association or epiphenomenon?

Recent literature data show a certain relation between Crohn's disease and celiac disease. We describe herein what are the pro and the cons about a possible association between Crohn's disease and celiac disease.     

Tumor necrosis factor and cancer, buddies or foes?

Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK). NF-kappaB is a major cell survival signal that is anti-apoptotic, whereas sustained JNK activation contributes to cell death. The crosstalk between the NF-kappaB and JNK is involved in determining cellular outcomes in response to TNF. In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates the growth, proliferation, invasion and metastasis, and tumor angiogenesis of cancer cells. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-kappaB, by combined therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in cancer biology with specific emphasis on carcinogenesis and cancer therapy.     

Serotonin and depression: pathophysiological mechanism or marketing myth?

The notion that impaired serotonin (5-HT) function can lead to clinical depression has a long history but is still controversial. Some have argued that the 5-HT hypothesis has been misused by the pharmaceutical industry to promote a simplistic biological model of depression to market selective serotonin reuptake inhibitors (SSRIs) to medical practitioners and the public. By contrast, there is now substantial evidence that unmedicated depressed patients have abnormalities in brain 5-HT function; however, the relation of these abnormalities to the clinical syndrome is unclear. The best evidence that 5-HT contributes to the pathophysiology of depression comes from studies of tryptophan depletion, which show that lowering brain 5-HT levels can induce acute symptomatic relapse in recovered depressed patients. Clarification of the mechanism of this effect will enable an understanding of how impaired 5-HT activity contributes to the subjective experience of depression.     

Acute severe colitis: infliximab and/or cyclosporine?

Acute severe ulcerative colitis is a serious condition that requires early hospitalization, with intensive monitoring and treatment. Despite the recent progress in the medical approach of Inflammatory Bowel Diseases acute severe ulcerative colitis remains a clinical challenge, with a mortality rate of nearly 1%. As of today, I.V. corticosteroids remain the 1(st)-line therapy for this complication. For non-responders (up to one-third of patients) possible options are surgery - whose timing is a critical point in the overall management of the disease - or rescue therapy with 2(nd)- line agents such as Cyclosporine and Infliximab. Here we will review the published studies dealing with the use of these medications in acute severe ulcerative colitis.     

Symptoms or side effects? Methodological hazards and therapeutic principles

The case is described of a 40 year old man with delusions and hallucinations, who at the start of this study was taking doses of neuroleptic medication greatly in excess of those that have been demonstrated to be optimally effective. Over 48 weeks, using PQ methods and detailed interviewing, his progress was charted as the medication was reduced to more appropriate levels. Across this change, his delusional beliefs remained unchanged, but there were substantial reductions in auditory hallucinations, as well as in hopelessness and anxiety. The case has implications for concepts of therapy in the psychoses and for the methodology of therapy studies. It also illustrates possible benefits of using PQ or other self-assessment methods as a means of calibrating therapy and perhaps enhancing compliance. © 1998 John Wiley & Sons, Ltd.