Outcomes,performance, and quality-What's the difference?

Calls for greater accountability within the addiction treatment field have led to a wide range of efforts designed to improve treatment performance, quality, and outcomes. However, efforts with conceptually and methodologically different approaches have used the same umbrella terms such as “quality,” “performance indicators,” and “outcome domains,” causing substantial confusion among providers and policymakers. This article provides operational definitions of the terms used in discussing quality, performance, and outcomes, as well as a discussion of ways to integrate efforts to measure treatment system performance and quality during treatment with patient outcomes during and following treatment. This article thus helps build a common understanding about how these efforts to bring greater accountability can be combined and integrated to improve the attractiveness and effectiveness of addiction treatments.     

Is it the Taste or the Buzz? Alexithymia,Caffeine, and Emotional Eating

Background: Alexithymia, a relatively stable personality trait characterized by difficulties identifying and describing feelings and externally oriented thinking, has been linked to both substance use disorders and eating disorders. In nonclinical samples, alexithymia is associated with heavier consumption of alcohol and caffeine. Both are psychoactive drugs, but unlike most drugs they are typically consumed in the context of palatable and calorie-rich products. Objectives: Given the association of alexithymia with disordered eating, the present study evaluated the hypothesis that heavier consumption of caffeine by those with high levels of alexithymia may be motivated by the palatable and caloric aspects of common caffeine products rather than by drug-seeking. Methods: There were 224 participants aged 17–63?years who completed instruments assessing demographics, alexithymia, emotional eating, caffeine consumption, alcohol consumption, negative moods, and reward sensitivity. Results: As predicted, alexithymia was positively related to emotional eating as well as consumption of caffeine and alcohol, and alexithymia was a significant predictor of caffeine intake in regression models. However, there was no indication of mediation by emotional eating. Conclusions: Alexithymia is characterized by deficient emotion regulation and negative moods, hence use of drugs and/or foods to regulate emotions, combined with poor interoceptive awareness, may account for excessive consumption of drugs or foods as alternative emotion regulation strategies in those with high levels of this trait.     

Action of prostaglandin,PGF2α, on the uterus of the pregnant rat

Summary The effects of prostaglandin F₂ (PG) have been studied on the transmembrane potentials and contractions in isolated myometrial strips from pregnant rats. The results showed that: 1. The sensitivity of the myometrium to exogenous PG increases from day 19 to day 22 of gestation. 2. The electrical response to PG, at maximally effective doses (10^–6 to 10^–5 M) consists of a slow depolarization which upon reaching threshold initiates spike discharge. 3. These actions are most pronounced t term (day 22) and are due to a direct action of PG on the myometrical cells. 4. D-600 (a methoxy derivative of verapamil) abolishes spike discharge and the phasic contractions induced by PG but has no effect on the slow depolarization and the accompanying increase in tonic tension. 5. The slow depolarization is dependent upon the presence of sodium in the external environment and is unaffected by the removal of calcium. 6. The spikes (and phasic contractions) are dependent upon the presence of calcium in the external environment.This study was supported by USPHS Grant HD-06963-9     

COX-2 expression in atherosclerosis: the good, the bad or the ugly?

Cyclooxygenase (COX) is the rate limiting enzyme catalyzing the conversion of arachidonic acid into prostanoids, lipid mediators critically implicated in a variety of physiological and pathophysiological processes, including inflammation, vascular and renal homeostasis, and immune responses. Since the early 1990s it has been appreciated that two isoforms of COX exist, referred to as COX-1 and COX-2. Although structurally homologous, COX-1 and COX-2 are regulated by two independent and quite different systems and have different functional roles. In the setting of acute ischemic syndromes it has been recognized that COX pathway plays an important role; however, whereas the function of platelet COX-1 in acute ischemic diseases is firmly established, the role of COX-2 in atherothrombosis remains controversial. The complex role of COX-2 in this setting is also confirmed by the unexpected cardiovascular side effects of long-term treatment with COX-2 inhibitors. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, the effects of the variable expression of upstream and downstream enzymes in the prostanoid biosynthesis on COX-2 expression and inhibition.     

A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, β-carbolines,and phenobarbitone

Summary The potent benzodiazepine receptor ligands -carboline-3-carboxylic acid ethyl ester (-CCM) and the corresponding methylester (-CCM) administered i.v. depressed segmental dorsal root potentials in spinal cats, reversed the prolongation of dorsal root potentials by phenobarbitone, and abolished the depression of a motor performance task induced by phenobarbitone in mice; -CCE enhanced the low-frequency facilitation of pyramidal population spikes in the hippocampus of anaesthetized rats. These effects of -carbolines reflect a depression of GABAergic synaptic transmission and, thus, are diametrically opposed to the enhancing action of benzodiazepine tranquilizers. The specific benzodiazepine antagonist, Ro 15-1788, while not affecting dorsal root potentials, hippocampal population spikes or phenobarbitone-induced motor performance depression, abolished the effects of -CCE on the three parameters and similar effects of -CCM on the spinal cord and motor performance.A three-state model of the benzodiazepine receptor is proposed in which benzodiazepine tranquilizers act as agonists enhancing the function of the benzodiazepine receptor as a coupling unit between GABA receptor and chloride channel, -carbolines act as inverse agonists reducing this coupling function, and Ro 15-1788 represents a competitive antagonist blocking both the enhancing effect of agonists and the depressant effect of inverse agonists on GABAergic synaptic transmission.     

The role of α2-adrenoceptor antagonism in the anti-cataleptic properties of the atypical neuroleptic agent,clozapine, in the rat

1. The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat.
2. The close structural analogues of clozapine, loxapine (0.1 mg kg⁻¹ s.c.) and iso-clozapine (1 and 3 mg kg⁻¹ s.c.) induced catalepsy in rats. In contrast, clozapine and the regio-isomer of loxapine, iso-loxapine (up to 10 mg kg⁻¹ s.c.) did not produce catalepsy, but at a dose of 1 mg kg⁻¹ significantly inhibited catalepsy induced by loxapine (0.3 mg kg⁻¹ s.c.).
3. Radioligand binding assays showed that cataleptogenic potential was most clearly predicted by the D₂/5-HT_1A, D₂/5-HT_1B/1D and D₂/α₂-receptor affinity (K_D) ratios: i.e. 30–100-fold higher ratios were calculated for loxapine and iso-clozapine, whereas the ratios were less than 1 for clozapine and iso-loxapine. The ratios of affinities for D₂ to 5-HT_2A, 5-HT_2C or D₁ did not reflect the grouping of cataleptic and non-cataleptic compounds.
4. Co-treatment with the α₂-adrenoceptor antagonists, yohimbine (1–10 mg kg⁻¹ s.c.), RX 821002 (1–10 mg kg⁻¹ s.c.) and MK-912 (0.3 and 1 mg kg⁻¹ s.c.) dose-dependently inhibited the cataleptic response to loxapine (0.3 mg kg⁻¹). Yohimbine (1–10 mg kg⁻¹ s.c.) also dose-dependently inhibited the cateleptic response to haloperidol (0.3 mg kg⁻¹ s.c.). The α₂-adrenoceptor antagonists had no effect per se.
5. Neither yohimbine (10 mg kg⁻¹) nor RX821002 (3 mg kg⁻¹) altered the cataleptic response to the D₁ receptor antagonist, SCH 23390 (1 mg kg⁻¹ s.c.), while, like clozapine, both compounds abolished the response to the 5-HT_2A receptor antagonist, MDL 100,151 (3 mg kg⁻¹ s.c.).
6. The present data strongly implicate α₂-adrenoceptor blockade in the anticataleptic properties of clozapine and suggest that its lack of extrapyramidal side effects in the clinic may also be a consequence of this property.

     

Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP,but not of the neurosteroid 3α,5β-pregnanolone in the rat

Rationale As sex steroids modify the number and distribution of brain -aminobutyric acid (GABA)_A receptor subunits, we investigated the potential modulation of anesthesia, induced by agents acting on the GABA_A receptor, by estrogen and androgen.Objectives To assess possible effects of sex and hormonal condition (i.e., intact vs castrate; estradiol vs testosterone treatment) on the anesthetic effect of a GABA_A agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4,-c]pyridin-3-ol hydrochloride), and an allosteric modulator of the GABA_A receptor: 3-hydroxy-5-pregnan-20-one (epipregnanolone).Methods The potencies of THIP and epipregnanolone for inducing loss of the righting response were compared between: (a) female and male rats; (b) intact and castrated animals of each sex; (c) untreated castrates and castrates given estradiol or testosterone.Results Sex and endocrine condition influenced sensitivity to i.v. THIP for the induction of anesthesia. ED₅₀ values were: gonadectomized females, 80 mg/kg > intact males, 50 mg/kg > proestrous females, 35 mg/kg > gonadectomized males, 28 mg/kg. Estradiol benzoate (EB; 3 g/day for 5 days) significantly increased THIP sensitivity in gonadectomized females: THIP + EB: ED₅₀=26 mg/kg vs THIP + sesame oil: ED₅₀=94 mg/kg, while testosterone propionate (TP; 10 mg injected 24 h before THIP) decreased THIP sensitivity in orchidectomized males when compared with vehicle-injected animals (ED₅₀=72 mg/kg vs 22 mg/kg, respectively).Conclusions Results suggest that estrogen increases the density or availability of GABA_A receptor subtypes on which THIP acts, while testosterone exerts the opposite effect. Neither sex nor gonadal condition influenced the anesthetic action of epipregnanolone as a similar potency was found in intact and in gonadectomized males and females.     

Is Na+ required for the binding of dopamine, amphetamine, tyramine, and octopamine to the human dopamine transporter?

The role of Na(+) in the recognition of blockers by the dopamine transporter is accomodated by a model with a cation site that overlaps with the blocker binding domain, and a distal Na(+) site that interacts with this cation site and perhaps with the blocker binding domain itself. The present study addresses the application of this model to the recognition of substrates by the dopamine transporter, focusing on conditions that should reveal a stimulatory effect, if present, of Na(+) on substrate binding. Recognition was studied via the inhibition of binding of [(3)H]WIN 35,428 (2beta-carbomethoxy-3beta-(4-fluorophenyl) [(3)H]tropane), a cocaine analog, to the human dopamine transporter in human embryonic kidney 293 cells. Little or no changes in binding were noted for dopamine, d-amphetamine, p-tyramine, or dl-octopamine by increasing [Na(+)] from 2 mM to 20 mM with co-varying Br(-), both at pH 7.4 and 7.0. In 74-mM Tris-HBr or -HCl, only dopamine and d-amphetamine showed binding increases upon raising Na(+), leveling off with NO(3)(-) or SO(4)(2-) but not Br(-) as anion at approximately 60 mM Na(+), consonant with a partly stimulatory action of Br(-). An Na(+) free, low 5-mM Tris-HEPES buffer was used for studying Na(+) curves truly starting at 0 mM, and, with SO(4)(2-) as the anion, no stimulation of binding by Na(+) was observed. This suggested that the stimulations observed in high (74 mM) Tris(+) buffer by Na(+) were not a direct effect of Na(+) but rather a disinhibitory effect of Na(+) in removing Tris(+) inhibition that depended upon substrate. Tris(+) IC(50) values in Na(+) free buffer were not lower for dopamine and d-amphetamine than p-tyramine and dl-octopamine. No evidence was found for a stronger inhibitory effect of Na(+) for dopamine and dl-octopamine potentially offsetting Tris(+) disinhibition. All results together support the existence of a substrate domain overlapping with a cation site that also binds Tris(+); a distal Na(+) site interacts with this cation site and with the substrate domain by negative allosterism and is additionally impacted by Cl(-). Importantly, interactions between sites vary with the type of substrate, and, in membrane preparations, Na(+) is not required for, or stimulatory to, the binding of any of the four substrates studied unlike the binding of the cocaine analog WIN 35,428.     

Investigation of the venoconstrictor effect of 8′ hydroxydihydroergotamine,the main metabolite of dihydroergotamine,in man

Summary The time course of the venoconstrictor effect of dihydroergotamine and its main metabolite 8 hydroxy-dihydroergotamine was investigated in a placebo-controlled study in seven healthy male volunteers, after direct local infusion of 0.08 and 0.4 µg into superficial hand veins. Both dihydroergotamine and 8 hydroxy-dihydroergotamine elicited a similar, marked venoconstrictor effect. The time course of the venoconstrictor action was similar for both compounds; about one third of the effect was present at the end of the infusion, which lasted for 10 min, and it took about a further 20 min for the effect to reach its maximum. The effect then remained fairly constant for the rest of the period of observation of 180 min from the start of the infusion. The data indicate that the pharmacological activity of oral dihydroergotamine is due not only to the unchanged drug but also to its main metabolite, 8 hydroxy-dihydroergotamine, which occurs in plasma in concentrations about 5–7 times higher than those of dihydroergotamine itself. The absolute bioavailability of unchanged dihydroergotamine, therefore, does not reflect the markedly higher bioavailability of pharmacologically active drug.     

Chronic food restriction in rats augments the central rewarding effect of cocaine and the δ1 opioid agonist, DPDPE, but not the δ2 agonist, deltorphin-II

RATIONALE: There is some, albeit conflicting, evidence that 5-HT3 receptors might be involved in the actions of abused stimulants. Most studies have focussed on examinations of 5-HT3 antagonists; this might be due to a lack of high-affinity 5-HT3 agonists that readily penetrate the blood-brain barrier. OBJECTIVES: N-(3-Chlorophenyl) guanidine (MD-354) is a member of a novel class of 5-HT3 ligands developed in our laboratories. We have previously demonstrated that MD-354 can exert agonist effects and now further explore this action. METHODS: Rats (n=9) were trained to discriminate 2 mg/kg MD-354 from saline vehicle in a two-lever drug discrimination task (VI-15 s schedule of reinforcement). The actions of agents with 5-HT3 character were evaluated. The emetic and antiemetic actions of MD-354 were also examined using the shrew as test subject. RESULTS: Various agents with demonstrated 5-HT3 agonist properties substituted for the MD-354 stimulus (MD-354 ED50=0.5 mg/kg): quipazine (ED50=0.2 mg/kg), meta-chlorophenylbiguanide (mCPBG, ED50=1.4 mg/kg), 2-methyl 5-HT (ED50=4.5 mg/kg), 1-(2-naphthyl)biguanide (2-NBG, ED50=1.9 mg/kg), and N-(2-naphthyl)guanidine (2-NG, ED50=0.7 mg/kg). Administration of the training dose of MD-354 in combination with the 5-HT3 antagonists zacopride and tropisetron resulted in stimulus antagonism (AD50=0.02 mg/kg); administered alone, however, zacopride engendered 81% MD-354-appropriate responding (ED50=0.03 mg/kg). MD-354 was shown to produce an emetic effect in the shrew at very high doses (i.e., 40 mg/kg); however, when administered in combination with cisplatin, MD-354 behaved as an antiemetic agent at 10 mg/kg. CONCLUSION: Taken together, the results indicate that MD-354 is a 5-HT3 agonist and that it might be an agent with partial agonist activity.     

Binding of the antiretroviral drug, d-aspartate-β-hydroxamate on the NMDA receptor

d-Aspartate-β-hydroxamate (d-A β H) exhibits antiretroviral properties in vitro and in vivo. It has glutamate agonist properties at the N-methyl-d-aspartate (NMDA) receptor in neuronal cell cultures. This study characterizes its binding properties to the NMDA receptor by measuring its stimulating effect on N-(1-(2-thienyl)[(3)H]cyclohexyl)piperidine ([(3)H]TCP) binding to the ionic channel in rat brain membranes. d-A β H stimulated [(3)H]TCP binding in a dose-dependent manner but to a lower extent than glutamate, suggesting only partial glutamate agonist properties. In the presence of antagonists of the different effector sites of the NMDA receptor the affinity of d-A β H was competitively decreased by CGS-19755 and 7-chlorokynurenate and unaffected by arcaine. Among several d-A β H analogues VHS.125 behaved as a full NMDA agonist, but l- or d-glutamate γ-monohydroxamate (d-GH or l-GH) were without effect. This study shows that d-A β H has potential neurotoxic effects due to its direct interaction with the NMDA receptor and that analogues such as d-GH or l-GH may rather be used in humans.     

Beer,wine, and social anxiety: Testing the “self-medication hypothesis” in the US and Cyprus

The social anxiety literature often cites the self-medication hypothesis (SMH) to explain why socially phobic clients often present with alcohol problems. Based on some earlier hints that social anxiety and drinking might be related in a curvilinear way, we sought to examine the SMH to assess for possible non-linear relationships, and to examine whether cultural differences affect these relationships. We surveyed self-reported social anxiety, alcohol expectancies, and alcohol use in college students from Cyprus (N?=?127) and the United States (US) (N?=?697). Participants were college students with a mean age of 19.8. Results revealed that positive and negative expectations about alcohol use were predictive of drinking for students from both cultures. Cypriot students endorsed fewer positive and more negative expectancies regarding alcohol use than their US counterparts, and engaged in less binge drinking. Social anxiety in men was related to drinking via a curvilinear relationship, in which drinking peaks at moderate levels of social anxiety. Among men, those with highest levels of social anxiety in both cultures drink the least. For women, there was no relationship between social anxiety level and drinking behavior. These findings demonstrate the complexity of the relationship between social anxiety and alcohol use. Far from being a linear relationship, these two variables are related in a curvilinear fashion, for men. This should inform future research on the SMH.     

Ximelagatran, the new oral anticoagulant: would warfarin survive the challenge?

The last decade witnessed major advances in the prevention and treatment of venous as well as of arterial thrombosis. Limitations of existing anticoagulants led to the development of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor (DTI) that is given orally, without the need for close monitoring. This compound was tried in the treatment of active venous thromboembolism, and the results were encouraging. Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective trials compared ximelagatran with low molecular weight heparin or warfarin in prevention of venous thromboembolism in patients undergoing major orthopedic procedures. The results of these clinical trials are reviewed in this article. Because of certain safety concerns (increased liver enzymes, potential hepatonecrosis, and increased coronary events) ximelagatran has not yet been approved by the FDA. Additional studies may be required to address these concerns. Ximelagatran has been approved, however, by the European regulatory authorities for short-term thromboprophylaxis. The success of ximelagatran or other oral antithrombin agents would provide significant proof of the concept for the long-term use of oral antithrombins in the prevention and treatment of both arterial and venous thrombosis.     

Toxicology, Environmental Health, and the “One Health” Concept

The One Health concept promotes collaboration among veterinarians, physicians, scientists, and other professions to promote human, animal, and ecosystem health. One Health illustrates the interconnectedness and interdependence of human, animal, and ecosystem health. This concept has traditionally focused on zoonoses that are infectious diseases, not on chemical- or poison-related illnesses in animals and their relationship to the detection and prevention of human illness. The purpose of this article is to describe key experiences of scientists in the Health Studies Branch within the National Center for Environmental of Health of the Centers for Disease Control and Prevention in which the study of animal illness facilitated a public health investigation into an outbreak of chemicalassociated human disease. The experiences highlight how utilizing the One Health approach may improve chemical-associated outbreak investigations and facilitate appropriate intervention strategies. An appropriate One Health approach in toxicology and environmental health in outbreak settings should include consideration of the common environments and food sources shared by humans and animals and consideration of the potential for contaminated animal products as food sources in human exposures.