Muscle contraction-induced steal model in the anesthetized cat

The current study describes a model in the anesthetized cat which may be used to investigate pharmacological interventions for the treatment of vascular “steal” during muscle contraction. An artificial stenosis was placed around both the descending abdominal aorta and the left external iliac artery. Arterial blood flow was measured in the right and left external iliac and right femoral arteries. Contraction of the left hindquarters, induced by electrical stimulation of the left sciatic and femoral nerves, resulted in an increase of left iliac artery blood flow from 14.7 ± 2.0 to 30.5 ± 2.8 ml min⁻¹ (p<0.001). A simultaneous reduction of blood flow measured at the level of the right femoral artery (6.7 ± 0.1 to 4.5 ± 0.7 ml min⁻¹, p<0.01) was observed in the noncontracting hindlimb (y = 7.76 − 0.10x, correlation coefficient = −0.865). The magnitude of each response was reproducible within the same animal. Administration of 8-phenyltheophylline, a nonselective antagonist of adenosine receptors, reduced the functional hyperemia response within the left external iliac artery by 32% and reduced the “steal” from the vascular bed perfused by the right femoral artery by 21%.     

What is Controlled Drinking?

Different terms have been utilized to define the drinking dispositions of problem drinkers which are neither total abstinence nor overtly harmful. The main terms that have been used are “normal drinking”, “controlled drinking”, “non-problem drinking” and “attenuated drinking”. Each concept is considered and criticized and it is concluded that clinicians and researchers need to be very aware of the overlap that exists between the different definitions. It is concluded that the greatest value that has been achieved from the advent of controlled drinking treatment and the ensuing debate is not that another treatment option has been developed, but that the perception of alcohol related problems has been changed to encompass the drinking of the population as a whole.     

Serotonin receptor blockade potentiates behavioural effects of beta-phenylethylamine

The 5-hydroxytryptamine (5HT) receptor blocker, methysergide (10 mg/kg), was found to potentiate the behavioural effects of β-phenylethylamine (PEA) (at doses between 20 and 60 mg/kg) on food reinforced schedule-maintained behaviour in two separate experiments involving a fixed interval 2 min schedule and a fixed ratio 20 schedule. Potentiation caused a parallel shift to the left in the log dose/response curve for suppression of responding induced by phenylethylamine, and was observed in both male and female rats. These data contrast with recent reports indicating that inhibition of functioning of 5HT systems blocks the effects of phenylethylamine in inducing the “Serotonin behavioural syndrome” (Sloviter et al., 1980a; Dourish, 1981). However, the potentiation reported here is compatible with frequent reports indicating that behavioural effects of amphetamine (-methyl-PEA) can be potentiated by reduction in 5HT functioning and are thus compatible with the hypothesis that phenylethylamine is a potential “endogenous amphetamine”.     

Heroin smoking by “chasing the dragon” in young opiate users in Ireland: stability and associations with use to “come down” off “Ecstasy”

We explored the frequency of commencing opiate use by “chasing the dragon” to “come down” off Ecstasy and the stability of heroin smoking in young opiate takers by assessing 102 subjects in Dublin using a semistructured interview. Ninety-two subjects had used Ecstasy. Of these, 68 reported “chasing” to “come down” off Ecstasy at some point in their history and were found to have used Ecstasy more frequently and in larger amounts. Thirty-six reported that their first experience of using opiates was to “come down” off Ecstasy, 28 citing this as their main reason for commencement.

Eighty-six of the 102 commenced opiates by “chasing” heroin, 61 of whom progressed to injecting after a mean of 2.9 years. This was associated with starting illicit drug use earlier, starting heroin earlier, and a history of using Ecstasy. Implications for service planners in developing responses to illicit drug use among adolescents are discussed.     

Examination of the inflammatory effect of ricin with special reference to the endogenous corticosteroid mobilisation

Ricin has been shown to produce a powerful inflammatory effect after subcutaneous injection. Parenterally administered ricin causes marked changes in the microcirculation, i.e., aggregation of red blood cells (“sludge-formation”) and increased permeability of small blood vessels. Ricin reduces the effect of another locally inflammatory agent, dextran. Further experiments using histological and spectrophotofluorimetric methods showed that the administration of ricin may constitute a strong stress for the organism resulting in mobilization of corticosteroids from the adrenals.     

Dynamic monitoring of glutathione redox status in UV-B irradiated reconstituted epidermis: effect of antioxidant activity on skin homeostasis

An “oxidative stress” should be considered as the consequence of a disbalance within the cutaneous tissue, between pro-oxidant processes and effective antioxidant defence systems and finally the result of a detrimental disturbance of the “cellular redox homeostasis”. Instead of monitoring some particular impairment or a specific biological target of oxidative stress, it is preferable to examine the global effect of a stress, which is revealed by a loss of cellular homeostasis. The measurement of glutathione (relative amount of reduced (GSH), an oxidized form (GSSG)), offers a suitable approximation of the cellular redox status,since glutathione plays a pivotal role in the biological antioxidant systems. It is involved in the “first line “ defence systems but also in repairing and recycling systems. This work aimed to develop an in vitro model that enables the dynamic monitoring of the glutathione redox status after UV-B irradiation. The method was performed in a commercially available Reconstituted Human Epidermis (RHE) model characterized by an high histo-morphological correspondance with normal human skin and by a very good inter batch reproducibility. With this experimental design it was possible to assess both the “physiological “ behaviour of the epidermis after irradiation and also the ability of a tested ingredient to preserve or to restore the redox cutaneous homeostasis. The epidermis were irradiated and allowed to different recovery time (1,5,8,24 h) After each recovery time the quantification of GSH and GSSG by HPLC has been performed on RHE homogenates prepared in carefully controlled conditions. A series of non treated epidermis has been used as reference control. The redox homeostasis loss (e.g. GSH depletion) has been observed immediately after irradiation and remained between 1 and 5 h, although partial recovery takes place. In the presence of antioxidant actives the GSH depletion was minimised, and a faster restoration of homeostasis has been observed. The GSH/GSSG ratio was differentially modified by the actives tested, providing important insights into their specific mechanism of action. The glutathione redox status appears a very sensitive sensor, and kinetic studies have correlated protection against oxidative stress with redox homeostasis preservation.     

Three simultaneous dissolution profiles on a solid pharmaceutical formulation by a FIA manifold provided with a single spectrophotometric detector

This article deals with the simultaneous determination of three dissolution profiles in the same pharmaceutical formulation. The officially proposed procedure from the pharmacopoeias is adapted to the FIA methodology to obtain the officially recommended profile or “global profile”, and two “individual” profiles, corresponding to dissolution rate of two different active principles present in the formulation; both drugs have overlapped UV–vis spectra. The simultaneous determination of several profiles is based on the derivative spectra and the zero crossing mathematical procedure for the “individual” profiles of an active principle; the “global” profile of the formulation is obtained from the order zero derivative. The empirical profiles were adjusted by regression analysis using the three-parameter (Higuchi equation) plot method which was selected as the most suitable. The analytical errors when the concentration of one drug is very small or very high are also checked.     

Journey through the K-hole: phenomenological aspects of ketamine use

Although recreational use of the dissociative anaesthetic drug ketamine is currently increasing, little is known about the phenomenological aspects of its use. We therefore designed a structured interview to examine initiation experiences, positive and negative effects of ketamine use, and concerns about the drug and its long-term effects. Ninety participants (30 frequent users, 30 infrequent ‘recreational’ users and 30 ex-users who had abstained from use for at least 3 months) were interviewed and reported drug use was verified by hair sample analysis. The most appealing aspects of ketamine for two-thirds of users were “melting into the surrounding”, “visual hallucinations”, “out-of-body experiences” and “giggliness”. Unappealing effects for half of users were “memory loss” and “decreased sociability”. Frequent ketamine users expressed more concerns than other groups about long-term effects on physical health problems, especially K-cramps and cystitis, whereas ex-users were more concerned about mental health problems. Addictive/dependent patterns of behaviour were also a concern: the majority of frequent users reported using the drug without stopping until supplies ran out and the mean increase in dosage in this group was six-fold from initiation to current use. We have identified specific health issues which seem uniquely related to ketamine use. Additionally, the dependence on ketamine frequently reported by users may be a cause for concern as its popularity grows and substance misuse services should be made aware of this when clients present in the future.     

Heroin and cocaine craving and use during treatment: measurement validation and potential relationships

Although commonly assessed with unidimensional scales, craving has been suggested to be multifaceted and to have a complex relationship with drug use and relapse. This study assessed the consistency and predictive validity of unidimensional and multidimensional craving scales. At the beginning of a 12-week outpatient treatment trial, opiate users (n = 101) and cocaine users (n = 72) completed unidimensional visual analog scales (VASs) assessing “want,” “need,” and “craving” and multidimensional 14- and 45-item versions of the Cocaine Craving Questionnaire (CCQ) or Heroin Craving Questionnaire (HCQ). Spearman correlations between the VASs and the first-order factors from the 45-item CCQ/HCQ were .20–.40, suggesting that the two types of assessment were not redundant. Treatment dropout and in-treatment drug use were more frequently predicted by scores on the 14- or 45-item CCQ than by VAS ratings. Results suggest that the CCQ/HCQ and the 14-item CCQ provide information that unidimensional VASs do not.     

Binding of H-acetylcholine and C-γ-aminobutyric acid to subcellular fractions of the brains of differentially-housed mice

Subcellular fractions prepared from the brains of mice subjected to conditions of differential housing (“isolation” and “aggregation”) for 35–37 days provided evidence for envronmentally-induced changes in the “binding” of acetylcholine (ACh) and γ-aminobutyric acid (GABA) to cerebral structures. Using homogenizing fluids containing 4 mM NaCl ± 4 mM LiCl or 40 mM NaCl ± 40 mM LiCl, it was shown that: (1) the binding of ACh and GAA are qualitatively different in mouse brain; (2) Li⁺ affects GABA binding to a greater extent than that of ACh; (3) less GABA binds to particulate fractions containing nerve endings prepared from the brains of “isolated” mice than to those prepared from the brains of “aggregated” mice. Addition of LiCl to homogenizing media served to increase the significance of differences in GABA binding found between brain fractions from “isolated” and “aggregated” mice.     

Extreme discordant phenotype methodology: an intuitive approach to clinical pharmacogenetics

Pharmacogenetics represents “the study of variability in drug response due to heredity”. Of the more than six dozen pharmacogenetic differences described in the medical literature, the majority of these variations occurs in drug-metabolizing enzyme genes and others in drug receptor and drug transporter genes, whereas many others have not yet been explained on a molecular basis. It is clear that “drug efficacy” or “drug toxicity” represents a multiplex phenotype, i.e. interaction between the drug (or its metabolites) and the gene products (enzymes, receptors, other targets) of two, and usually many more than two, genes. Because there is a gradient in these phenotypes (efficacy or toxicity), it is extremely important to select patients having the most unequivocal phenotype possible—if one wishes to find the gene(s) responsible for the trait. The method of “extreme discordant phenotype” (EDP) is therefore highly recommended. Using EDP methodology, DNA sequence variants (genotype) can be unconditionally correlated with drug efficacy or toxicity (phenotype). EDP methodology is mathematically intuitive and, in essence, has been used in a number of previous clinical pharmacogenetic studies. This EDP approach should be applicable to virtually any pharmaceutical agent in patient populations.     

Alcohol controls and Aboriginal society: The effects of the Northern Territory restricted areas legislation

The “restricted areas” provisions of the Northern Territory Liquor Act constitute a preventative policy aimed at reducing the effects of alcohol abuse, particularly on Aboriginal communities. Under the provisions, communities can apply to be declared “dry” or semi-restricted with respect to liquor. Since their inception in 1979, the provisions have given rise to continuing controversy. This paper addresses some of the issues associated with the controversy. Patterns of alcohol consumption on “dry”, semi-restricted and unrestricted communities are compared, and the incidence of apprehension for public drunkenness before and after restricted area declarations is examined. The paper also discusses the provisions under which vehicles implicated in acts of illicit “grog-running” are forfeited to the NT Government. It is concluded that the restricted area provisions are associated with reduced levels of alcohol consumption and apprehensions for drunkenness, and are therefore beneficial in outcome. However, it is also argued that at present the provisions are flawed in that, while some aspects serve to promote community control over alcohol consumption, other elements have the effect of undermining community control and responsibility.     

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.     

Elevated urinary excretion of metallothionein due to environmental cadmiun exposure

Metallothionein, a low molecular weight cadmium-binding protein, has been determined for the first time in urine of “itai-itai” disease patients and other Japanese women environmentally exposed to cadmium. On a group basis, the urinary metallothionein levels of “itai-itai” disease patients and suspected patients were significantly higher than that of women living in a cadmium-polluted area. Women living in a non-polluted area excreted significantly less metallothionein than women living in a cadmium-polluted area. A similar trend was observed for urinary β₂-microglobulin, a non-specific index of renal tubular dysfunction. However, mean levels of urinary cadmium in the “itai-itai” disease patients, suspected patients and women living in the cadmium-polluted area were similar. It is suggested that if, in addition to β₂-microglobulin and cadmium, metallothionein is used as another index of cadmium exposure, monitoring of renal tubular dysfunction caused by cadmium may be more effectively carried out.     

Drugs and the media

“Drugs” are extremely newsworthy: each year they are the subject of literally thousands of items produced by the Australian media. Most of these items are repetitious, stereotypical and narrowly focused on crime, deviance and rectification. Illegal drug consumption by individuals and the efforts of medical and social welfare professionals to eradicate the “problem” so defined are the twin foci of the press and television. Legal substances (including tobacco and alcohol) are interpreted much more ambiguously, and are relatively infrequently the subject of journalistic analysis.

The media systematically ignore the historical, economic and industrial aspects of drug production and consumption.

“Drugs”, although habitually construed as the cause of “human” and “social” problems (and hence as necessitating administrative attention), seem strangely divorced from real political economic determinations. They serve as inexhaustabled pretexts for the proliferation of television current affairs items and newspaper features which seldom resist the image of the confessing, suffering victim. “Hard” news is preoccupied with reiterating the ritual drama of drug seizures and exposes of “organised” crime. Both the press and television educate their audiences to a resigned, alienated passivity.     

"Just using old works": injecting risk behaviour in prison

A minority of injecting drug users engage in high risk injecting behaviours when in prison. In the United Kingdom between a quarter and a third of injectors who enter prison inject when in prison, and of these about three-quarters share needles and syringes. In the present study, 44 drug injectors who had been released from prison for no longer than 6 months were recruited and interviewed in three geographical areas in England. Interviewees were asked to recount their experiences of drug use during their most recent period of imprisonment. The majority of interviewees were male (38/44), had a mean age of 28 years, with a mean age of 16 years at first drug use, were primarily opiate users (39) and had multiple imprisonments. All respondents reported drug use when imprisoned and drug injecting was reported by 16 interviewees. Most injected at irregular intervals and at a reduced level, compared with injecting when in the community. Nine reported using needles and syringes that others had previously used. When considering other injecting equipment, more sharing occurred than was actually reported. Much re-use of equipment was viewed simply as “using old works”. The sharing of “cookers” and “filters”, and drug sharing by “backloading” and “frontloading” were common. The concept of “sharing” tended to be understood by respondents as related to the use of tools of injection (needles and syringes rather than other equipment); the use of tools in the act of injection (rather than for mixing drugs); proximity (multiple use of needles and syringes in the presence of others); temporality (shorter time elapse between consecutive use of needles and syringes previously used by another) and source (hired rather than borrowed or bought). We conclude that syringe sharing is an integral part of drug use and drug injecting in prison. Many of those interviewed displayed a restricted understanding of what denotes syringe sharing. Our data reinforce the need for interventions and initiatives to be developed within prisons to deal with the considerable risk posed by continued injecting drug use.     

Aversive stimulus properties of drugs

A large number of psychoactive drugs have been considered to possess aversive stimulus properties, as demonstrated by their ability to induce conditioned taste aversion (CTA) in animals. However, the interpretation of the CTA effect is at present unclear. The hypothesis that drug-induced CTA is due to drug-induced conditioned “illness” is supported by the results of studies which implicate central emetic systems or their functional equivalents in the acquisition and recall of CTA induced by toxins. However, other data, obtained with agents which are not generally considered to be toxins, are not at present easily reconciled with this hypothesis. Conditioned taste aversion induced by self-administered drugs has been described as “paradoxical” in that some drugs will induce CTA at the same doses that maintain self-administration. A number of possible explanations for this apparent paradox are discussed, the majority of which are considered to be inadequate. The idea that the paradox of CTA induced by self-administered drugs is more apparent than real merits consideration. Possible relationships between studies of drug-induced CTA and operant studies of drugs as aversive agents are discussed. The most fruitful future avenues for research into the actions of drugs in the CTA procedure will probably be those that concentrate on providing answers to very basic questions such as whether or not drug-induced CTA is due to conditioned “illness”, and whether or not the phenomenon termed conditioned taste aversion actually involves conditioning with a drug-induced aversive stimulus.     

About the centrality of mood lowering in mood disorders : Plenary Lecture ECNP Congress, Monte Carlo, October 1991

5-HT disturbances in depression (as exemplified by lowered CSF 5-HIAA) are not syndrome specific but related to components of the depressive syndrome, specifically to increased anxiety and aggression. These 5-HT disturbances are probably core pathogenetic processes not derivative features. I hypothesized that in this subtype of depression, i.e. in “5-HT related depression”, the key psychopathological disturbances are dysregulation of anxiety and aggression, while mood lowering is a “by-product”. Based on this hypothesis it was predicted that agents which ameliorate anxiety and/or aggression via harmonization of 5-HTergic transmission will, in addition, exert overall antidepressant effect in “5-HT related depression”. The study of the relative “weight” of the various psychopathological components of depression is a basic exercise in understanding the nature of that condition and could, as such, greatly facilitate the goal-directed search for new and innovative antidepressants.