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INTRODUCTION: Despite public policies and legislative changes aiming to curtail men's violence against women (VAW) around the world, women continue to be exposed to VAW throughout their life. One in three women in Europe has reported physical or sexual abuse. Men who display unequitable masculinities are more likely to be perpetrators. VAW is increasingly appearing at younger ages. The aims of the project are fourfold: (1) to explore and position the discourses that young people (men and women, 18-24 years) in Sweden, Spain, Ireland and Israel use in their understanding of masculinities, (2) to explore how these discourses influence young people's attitudes, behaviours and responses to VAW, (3) to explore individual and societal factors supporting and promoting anti-VAW masculinities discourses and (4) to develop actions and guidelines to support and promote anti-VAW masculinities in these settings. METHODS AND ANALYSIS: A participatory explorative mixed-method study will be used. In Phase 1, qualitative methods will be used to identify the discourses that young people and stakeholders use to conceptualise masculinities, VAW and the actions that are needed to support and promote antiviolence masculinities. In Phase 2, concept mapping will be used to quantify the coherence, relative importance and perceived relationship between the different actions to support and promote anti-VAW masculinities. Phase 3 is a knowledge creation and translation phase, based on findings from Phases 1 and 2, where actions and guidelines to promote and support anti-VAW masculinities will be developed. ETHICS AND DISSEMINATION: Ethical clearance has been obtained from ethics review boards in each country. Results will be disseminated through peer-reviewed publications, presentations at international conferences, policy briefs, social media and through the project online hub. With its multicountry approach, our project results seek to inform policies and interventions aimed at promoting discourses which challenge hegemonic masculinities.

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A 56-year-old male was treated by local surgery in 1968 and 2005 for a left thigh lesion. A 2nd local relapse occurred in 2015 and was treated by complete macroscopic surgery with histology concluding to a hidradenocarcinoma. A 3rd locoregional relapse occurred in October 2018, with the presence of inflammatory ulcerated lesions. A 2nd histology and immunohistochemistry exam showed a proliferation positive for CK, CK5, and p63 suggesting the diagnosis of hidradenocarcinoma. The patient was treated by 3 lines of chemotherapy, 1st by Adriamycin, 2nd by carboplatin-paclitaxel, and then 3rd by oral capecitabine, leading to a stable clinical disease but without a clinical benefit. A locoregional plus metastatic lung progression was observed in March 2019, with the presence of lung nodules and retroperitoneal lymph nodes, multiple skin left thigh and left inguinal ulcerated lesions. The patient received then in 4th line in April 2019 oral sunitinib at 50 mg daily, with 4 weeks therapy/2 weeks pause. Side effects were represented by mucositis, anorexia, weight loss, and fatigue. We observed since the 1st week of therapy a fast response, with a decrease of the ulcerated lesions, a skin loss, and deep hemorrhagic areas. CT-scan showed after 2 weeks of sunitinib an objective response on both locoregional and metastatic lesions.

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Purpose. To report the annual hazard of relapse in stages II and III colorectal cancer (CRC) Tunisian patients treated with curative intent. We also aim to evaluate impact of oxaliplatine according to anatomo-clinical features. Methods. We collected data about clinico-pathological parameters of 331 CRCs. We analyzed annual hazard of recurrence (locoregional and/or distant) of the overall population and several subgroups: colon cancer vs rectal cancer and stage II vs stage III. We also analyzed impact of adjuvant oxaliplatine on recurrence within these subgroups. Results. Relapse rate was 38.1%, with a mean time to relapse of 27.6 months. We noted 23.8% local recurrence, 69.8% distant recurrence, and 6.4% both. We observed higher local relapse rate in rectal cancer (26.8 vs 3.2%) vs colon cancer (p = 0.004). Stage III had a higher metastatic relapse rate vs stage II (31.6 vs 20.8%, p = 0.043). Annual hazard of recurrence for the overall population showed two peaks: [1-2] year-interval by 10.1% and [3-4] year-interval by 11.3%. Stage III showed significantly higher and earlier recurrence hazard peak compared to stage II (16.3 vs 8.1% in [1-2] year-interval). Oxaliplatine significantly improved annual hazard of recurrence in each year-interval from year 1-4, in colon cancer and in stage III but without impact in rectal cancer and stage II. Conclusion. Extended follow-up to 4 years should be considered in Tunisian population. Impact of oxaliplatine showed same features to reported occidental series (AU)

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PURPOSE: To report the annual hazard of relapse in stages II and III colorectal cancer (CRC) Tunisian patients treated with curative intent. We also aim to evaluate impact of oxaliplatine according to anatomo-clinical features. METHODS: We collected data about clinico-pathological parameters of 331 CRCs. We analyzed annual hazard of recurrence (locoregional and/or distant) of the overall population and several subgroups: colon cancer vs rectal cancer and stage II vs stage III. We also analyzed impact of adjuvant oxaliplatine on recurrence within these subgroups. RESULTS: Relapse rate was 38.1%, with a mean time to relapse of 27.6 months. We noted 23.8% local recurrence, 69.8% distant recurrence, and 6.4% both. We observed higher local relapse rate in rectal cancer (26.8 vs 3.2%) vs colon cancer (p = 0.004). Stage III had a higher metastatic relapse rate vs stage II (31.6 vs 20.8%, p = 0.043). Annual hazard of recurrence for the overall population showed two peaks: [1-2] year-interval by 10.1% and [3-4] year-interval by 11.3%. Stage III showed significantly higher and earlier recurrence hazard peak compared to stage II (16.3 vs 8.1% in [1-2] year-interval). Oxaliplatine significantly improved annual hazard of recurrence in each year-interval from year 1-4, in colon cancer and in stage III but without impact in rectal cancer and stage II. CONCLUSION: Extended follow-up to 4 years should be considered in Tunisian population. Impact of oxaliplatine showed same features to reported occidental series.

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BACKGROUND: The objective of this study was to examine the relative contribution of factors explaining ethnic health inequalities (EHI) in poor self-reported health (pSRH) and limiting long-standing illness (LLI) between Health Survey for England (HSE) participants. METHOD: Using HSE 2003-2006 data, the odds of reporting pSRH or of LLI in 8573 Bangladeshi, Black African, Black Caribbean, Chinese, Indian, Irish and Pakistani participants was compared with 28,470 White British participants. The effects of demographics, socioeconomic position (SEP), psychosocial variables, community characteristics and health behaviours were assessed using separate regression models. RESULTS: Compared with White British men, age-adjusted odds (OR, 95% CI) of pSRH were higher among Bangladeshi (2.05, 1.34 to 3.14), Pakistani (1.77, 1.34 to 2.33) and Black Caribbean (1.60, 1.18 to 2.18) men, but these became non-significant following adjustment for SEP and health behaviours. Unlike Black Caribbean men, Black African men exhibited a lower risk of age-adjusted pSRH (0.66, 0.43 to 1.00 (p=0.048)) and LLI (0.45, 0.28 to 0.72), which were significant in every model. Likewise, Chinese men had a lower risk of age-adjusted pSRH (0.51, 0.26 to 1.00 (p=0.048)) and LLI (0.22, 0.10 to 0.48). Except in Black Caribbean women, adjustment for SEP rendered raised age-adjusted associations for pSRH among Pakistani (2.51, 1.99 to 3.17), Bangladeshi (1.85, 1.08 to 3.16), Black Caribbean (1.78, 1.44 to 2.21) and Indian women (1.37, 1.13 to 1.66) insignificant. Adjustment for health behaviours had the largest effect for South Asian women. By contrast, Irish women reported better age-adjusted SRH (0.70, 1.51 to 0.96). CONCLUSIONS: SEP and health behaviours were major contributors explaining EHI. Policies to improve health equity need to monitor these pathways and be informed by them.

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AIM: We investigated the prognostic significance of intraductal carcinoma of the prostate (IDC-P) in biopsies and transurethral resections prior to external beam radiotherapy with or without androgen deprivation. METHODS: Cohort 1 consisted of 118 intermediate risk prostate cancer patients treated by radiotherapy, with biochemical relapse as primary end-point (median follow-up 6.5 years). Cohort 2 consisted of 132 high risk patients, enrolled in a phase III randomised trial (EORTC 22863) comparing radiotherapy alone to radiotherapy with long-term androgen deprivation (LTAD) with clinical progression free survival as primary end-point (median follow-up 9.1 years). Presence of IDC-P was identified after central review. Multivariable regression modelling and Kaplan-Meier analysis were performed with IDC-P as dichotomous variable. RESULTS: IDC-P was a strong prognosticator for early (<36 months) biochemical relapse (HR 7.3; p = 0.007) in cohort 1 and for clinical disease-free survival in both arms of cohort 2 (radiotherapy arm: HR 3.5; p < 0.0001; radiotherapy plus LTAD arm: HR 2.8, p = 0.018). IDC-P retained significance after stratification for reviewed Gleason score in the radiotherapy arm (HR 2.3; p = 0.03). IDC-P was a strong prognosticator for metastatic failure rate (radiotherapy arm: HR 5.3; p < 0.0001; radiotherapy plus LTAD arm: HR 3.6; p = 0.05). CONCLUSIONS: IDC-P in diagnostic samples of patients with intermediate or high risk prostate cancer is an independent prognosticator of early biochemical relapse and metastatic failure rate after radiotherapy. We suggest that the presence of IDC-P in prostate biopsies should routinely be reported.

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We compared the analgesic and anaesthetic efficacy of pudendal nerve block with that of dorsal penile nerve block in male patients aged 3-5 years of age, undergoing elective circumcision. Thirty patients had a nerve stimulator-guided pudendal nerve block with two separate injection points 1.5-2 cm from the centre of the anus, and thirty patients received a dorsal penile nerve block. The same total anaesthetic volume of 0.3 ml.kg(-1) was used in both groups. The pudendal nerve group showed significantly lower postoperative pain scores than the dorsal group (SD) (p < 0.05), and significantly fewer patients consumed analgesics in the pudendal group than the dorsal group: 0 vs 5 (17%) at 0 and 6 h, respectively. This study demonstrates the effectiveness of pudendal nerve block in comparison to the dorsal nerve block, with improved postoperative outcomes in children undergoing circumcision.

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BACKGROUND: Few studies have examined the explanatory pathways to social inequalities in health within ethnic minorities. The current study examined the relative contributions of specific pathways explaining the associations between socioeconomic status (SES) and limiting longstanding illness (LLI) among the Arab minority in Israel. METHODS: A cross-sectional study of a random sample of 902 individuals aged 30-70 selected in a multistage sampling procedure. SES was measured by education, land ownership and relative family income. Five-stage logistic regressions assessed the attenuations in the odds of LLI among those with lower SES compared to higher SES after including relevant groups of explanatory factors: psychosocial, behavioural and community, and their integration. RESULTS: Rates of LLI were significantly higher in participants with lower SES. Inclusion of groups of explanatory variables attenuated all SES-LLI associations in a similar pattern: psychosocial factors played a main explanatory role, yielding 15-40% attenuation in odds ratios (OR). The contribution of community indicators was modest (10-21%); health behaviours had a marginal contribution (6-7%). Cultural factors were not associated with SES or LLI. The integrative model contributed up to 49% reduction in the OR. CONCLUSIONS: The significant associations between SES and LLI suggest that formative policy to reduce SES-LLI disparities should emphasise creating opportunities for economic development to improve SES, which was the main predictor of inequalities. Combining strategies of community capacity building and reinforcement of individual inner resources might be complementary. Such conclusions might apply to other minorities in a similar context, for which future studies are required.

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AIMS/HYPOTHESIS: Obesity is associated with insulin resistance and inflammation. The circulating human mononuclear cell (MNC) has been shown to respond to low-dose insulin infusion. We have now investigated whether in obesity: (1) phosphorylated insulin receptor beta subunit (p-INSR-beta) is reduced in the MNC; (2) pro-inflammatory mediators including inhibitor of kappa light polypeptide gene enhancer in B cells-kinase beta (IKBKB), suppressor of cytokine signalling-3 (SOCS) and protein kinase C-beta 2 (PRKCB2) are increased and related to p-INSR-beta; and (3) the reduction in MNC p-INSR-beta is related to the reduction in insulin sensitivity. MATERIALS AND METHODS: MNCs were prepared from fasting blood samples of 16 normal weight and 16 obese female subjects. RESULTS: Our data show that p-INSR-beta is reduced significantly in MNCs from obese subjects compared with that of normal controls. MNCs from obese subjects have higher IKBKB expression, increased nuclear factor kappa B (NFkappaB) binding and higher mRNA expression of TNFAIP1 and IL6 genes. NFkappaB binding, TNFAIP1 mRNA and plasma C-reactive protein are inversely related to p-INSR-beta. PRKCB2 mRNA and protein expression were significantly higher in the obese subjects and were related significantly to pro-inflammatory mediators but not to p-INSR-beta. SOCS3 mRNA expression was markedly elevated and positively related to pro-inflammatory mediators including IKBKB and PRKCB2 on the one hand and inversely related to p-INSR-beta on the other. CONCLUSIONS/INTERPRETATION: We conclude that in obesity the MNC is characterised by reduced p-INSR-beta and increased inflammatory mediators including IKBKB, PRKCB2 and SOCS3. The increase in SOCS3 but not IKBKB or PRKCB2 is related inversely to p-INSR-beta and might mediate the inhibition of p-INSR-beta. These data elucidate the relationship between inflammation and insulin resistance using the MNC as a model.

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The aim of this study was to compare the efficacy of nerve stimulator guided paravertebral block with ilio-inguinal nerve block in children undergoing inguinal herniorrhaphy. Eighty children were randomly allocated to receive either paravertebral block or ilio-inguinal nerve block. Each block was evaluated in terms of intra-operative haemodynamic stability, postoperative pain scores at rest, on movement and during activity, requirement for supplemental analgesia and parental satisfaction. Haemodynamic stability was maintained significantly better during sac traction in the paravertebral block group (p < 0.005). Pain scores and analgesic consumption were significantly lower in the paravertebral block group during the postoperative follow-up period (p < 0.05). Parental satisfaction (93%vs 69%) and surgeon satisfaction (93%vs 64%) were significantly higher in the paravertebral block group (p < 0.05). Paravertebral blockade improved and prolonged postoperative analgesia, and was associated with greater parental and surgeon satisfaction when compared to ilio-inguinal nerve block.

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Se estudiaron 187 pacientes, entre 2 - 72 meses, 104/187 (55.61 por ciento) varones y 83/187 (44.38 por ciento) hembras. 173/187 (92.51 por ciento) se incluyeron en el grupo A (evaluación temprana) y 14/187 (7.48 por ciento) en el B (evaluación tardía). En ambos, el cáustico ingerido principalmente fue el hidróxido de sodio (lejía) (52 por ciento y 21.43 por ciento, respectivamente). El hidróxido de sodio (soda caústica, easy off), el amoníaco, el ácido sulfúrico y la nieve carbónica (hielo seco) son los agentes productores de lesiones más severas en orofaringe y esófago. El grupo A presentó vómitos (48.55 por ciento), sialorrea (20.23 por ciento) y disfagia (10.40 por ciento), y el B disfagia (92.85 por ciento), vómitos (57.14 por ciento) y odinofagia (35.71 por ciento). A todos se les relizó endoscopia digestiva superior, dilataciones precoces en esofagitis grado II-III y dilataciones terapéuticas en los pacientes de evaluación tardía. El grupo A se resolvió con éxito. Ningún paciente ameritó intevención quirúrgica. Concluímos, que la endoscopia digestiva superior y las dilataciones precoces constituyen un método adecuado para manejar pacientes con lesiones sofágicas por cáusticos antes de las 48 horas de avolución

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OBJECTIVE: The authors reviewed the pathogenesis of cocaine-related cerebral ischemia, appraised current knowledge of its sequelae, and assessed the role of putative therapeutic agents, particularly dihydropyridine-class calcium channel antagonists. METHOD: The authors performed an OVID-based literature review of all indexed journals between 1966 and 2000. RESULTS: Cocaine abuse significantly increases the risk of ischemic stroke. The principal mechanism of cocaine-induced cerebral ischemia is vasospasm of large cranial arteries or within the cortical microvasculature. Increased levels of extracellular monoamines, particularly dopamine, mediate vasospasm. Neuroanatomical and labeling studies also have shown that dopamine-innervated neurons may regulate cerebral blood flow. Indeed, dopamine-rich brain regions appear to be relatively specific targets for cocaine-induced cerebral ischemia. Neuroimaging studies show that cocaine-induced hypoperfusion can persist even after 6 months of abstinence. Hypoperfusion can result in deficits on complex and simple psychomotor tasks but perhaps not on memory or attention. Severe cerebral ischemia can directly precipitate neuronal death and degradation, a condition exacerbated by liberation of the excitatory amino acid glutamate. Dihydropyridine-class calcium channel antagonists inhibit cocaine-mediated dopamine release on neurons involved in vasospasm and the control of cortical circulation. Other causes of cerebral ischemia include thrombogenesis and vasculitis. Although antithrombotic agents have potential in alleviating cocaine's neurotoxic effects, their use may be limited by the risk of spontaneous hemorrhage. CONCLUSIONS: Cocaine abuse can result in stroke, neuroischemia, and cognitive deficits that can persist even after prolonged abstinence. Dihydropyridine-class calcium channel antagonists, such as isradipine, show promise as therapeutic agents for preventing cocaine-induced cerebral ischemia.

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BACKGROUND: Recently, we showed by using self-report that combining ondansetron (4 microg/kg twice a day) and naltrexone (25 mg twice a day) was effective at reducing drinking and increasing abstinence among early-onset alcoholics (EOAs), who are characterized by a range of antisocial behaviors and high biological and familial disease predisposition. Here, we investigated whether the self-reported differences in drinking would be corroborated by measurements of serum carbohydrate-deficient transferrin (CDT) level, a sensitive, reliable, and well-validated marker of transient alcohol consumption. METHOD: An 8-week double-blind clinical trial was performed in which 20 EOAs were randomized to receive ondansetron (4 microg/kg twice a day) and naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized cognitive behavioral therapy. Serum CDT was assessed at weeks 0 (baseline), 4, and 8. RESULTS: Log serum CDT was significantly lower in the ondansetron and naltrexone group (group mean, 1.44 +/- 0.076) compared with the placebo group (group mean, 1.82 +/- 0.113), as evidenced by a main effect of group [F(1,15) = 7.2, p = 0.017; effect size = 0.32], visit [F(1,16) = 11.2, p = 0.004; effect size = 0.41], and an interaction between group and visit [F(1,16) = 27.54, p < 0.001; effect size = 0.63]. CONCLUSIONS: The combination of ondansetron plus naltrexone was superior to placebo at reducing serum CDT. This corroborated our self-reported drinking data and demonstrated that the medication combination is an effective treatment for EOAs.

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RATIONALE: Previously, we have reported that the combination of ondansetron (a 5-HT3 antagonist) and naltrexone (a mu opioid antagonist) appears to act synergistically at improving the drinking outcomes of early onset alcoholics (EOA). a subtype of alcoholic characterized by developing problem-drinking earlier, antisocial behaviors, high familial loading, and biological disease predisposition. Presumably, this medication combination counteracts the interaction between activated central 5-HT3 receptors and the endogenous opioid system during the mediation of alcohol-induced reward. We now hypothesize further that an important mechanism by which the combination diminishes alcohol consumption is through a reduction in craving. OBJECTIVE: To determine whether the combination of naltrexone and ondansetron is superior to a placebo at reducing craving among EOA, and the relationship between craving and drinking behavior in both treatment groups. METHODS: We conducted an 8-week double-blind placebo-controlled clinical trial in which 10 EOA were randomized to receive ondansetron (4 microg/kg b.i.d.) + naltrexone (25 mg b.i.d.) and 10 EOA had a placebo (total n=20) as an adjunct to weekly standardized group cognitive behavioral therapy. Craving was measured by using the obsessive compulsive drinking scale (OCDS). RESULTS: Craving ratings were scored on four subscales which where derived empirically by principal component structure analysis of the OCDS. EOA who received the medication combination, compared with the placebo, had significantly lower scores on "automaticity of drinking" and "alcohol consumption ". Reduction in automaticity of drinking was correlated with self-reported drinking for only the medication combination group. CONCLUSIONS: By reducing automaticity of drinking, the medication combination presumably decreased drinking salience and intensity. Larger scale studies testing these medications, both alone and together, among alcoholic subtypes are needed to establish and extend these promising findings.

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CONTEXT: Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent. OBJECTIVE: To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT(3) (serotonin) antagonist ondansetron. DESIGN: Double-blind, randomized, placebo-controlled clinical trial. SETTINGS: University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999). PARTICIPANTS: A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization. INTERVENTIONS: After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 microg/kg (n = 67), 4 microg/kg (n = 77), or 16 microg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy. MAIN OUTCOME MEASURES: Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption. RESULTS: Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 microg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P =.03, P =.01, and P =.02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P =.03, P =.004, and P =.03, respectively). Ondansetron, 4 microg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P =.02) and total days abstinent per study week (6.74 vs 5.92; P =.03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 microg/kg twice per day) compared with those who received the placebo (-0.17 and -0.19 vs 0.12; P =.03 and P =.01, respectively). CONCLUSION: Our results suggest that ondansetron (particularly the 4 microg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality. JAMA. 2000;284:963-971

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BACKGROUND: Individuals considered to be early onset alcoholics (EOA) are characterized by an early onset age, a broad range of antisocial behaviors, high familial loading, and presumed biological disease predisposition. Ondansetron, a 5-HT3 antagonist, improves drinking outcomes and increases abstinence rates among EOA. Individuals with high familial loading for developing alcoholism have lower levels of beta-endorphin and demonstrate a more pronounced increase in beta-endorphin levels in response to alcohol administration compared with individuals who do not have alcoholic relatives. The propensity for naltrexone (a mu opioid antagonist) to reduce alcohol's rewarding effects and drinking in humans is greatest in individuals with high familial loading. Predicated on the added knowledge that 5-HT3 receptors may themselves mediate alcohol reward via activation of the endogenous opioid system, we hypothesized that the combination of ondansetron and naltrexone would act synergistically and would be an effective treatment in EOA. METHODS: We conducted an 8-week double-blind placebo controlled clinical trial in which 20 EOA were randomized to receive ondansetron (4 microg/kg twice a day) + naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized group Cognitive Behavioral Therapy. RESULTS: At endpoint, subjects who received ondansetron + naltrexone (n = 10), compared with those who received placebo (n = 10), had fewer drinks/day (covariate adjusted mean 0.99 +/- 0.60 vs. 3.68 +/- 0.63; F1, 16 = 9.35,p = 0.008; effect size = 1.42), drinks/drinking day (covariate adjusted mean 3.14 +/- 0.87 vs. 6.76 +/- 0.71; F1, 13 = 10.45, p = 0.007; effect size = 1.71), and a trend toward increased percent days abstinent (covariate adjusted mean 69.76 +/- 8.64 vs. 48.24 +/- 9.12; F1, 16 = 3.58, p = 0.08; effect size = 0.88). CONCLUSIONS: Ondansetron plus naltrexone seems to synergistically improve the drinking outcomes of EOA. Larger scale studies that test these medications, both alone and together, among various alcoholic subtypes are needed to establish and extend these promising findings.

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Preclinical studies have exploded our knowledge about the behavioral and biological underpinnings of alcoholism. These studies suggest that certain neurotransmitters, particularly those interacting with the opioid, N-methyl-D-aspartate, and monoamine systems, may play a critical role in the expression of alcohol-drinking and other behaviors associated with its abuse liability. Built upon this foundation, important advances have been made in the development of therapeutic medications for the treatment of alcoholism. Of the medications reviewed, acamprosate's potential appears to be the most widely established. In the USA, naltrexone was approved by the Food and Drug Administration in 1995 for the treatment of alcoholism; however, the results of some studies have been less encouraging. Naltrexone's reliance on high compliance rates for efficacy may, eventually, limit its potential in clinical settings offering generic treatment for alcoholism. The relative paucity of dose-response studies on naltrexone's effects in treating alcoholics is an important gap in the literature. Recent data from a large clinical trial suggests that ondansetron, a serotonin3 antagonist, offers new hope for the treatment of early onset alcoholics; a type of alcoholism most difficult to manage with psychosocial measures alone. Different subtypes of alcoholic may, therefore, have varying treatment responses to serotonergic agents. Matching subtypes of alcoholic to effective treatment medications based upon their different biologies remains an important therapeutic goal. Combinations of effective pharmacological agents need exploration as they may prove to be synergistic, and could shepherd in a new era of treatments aimed at multiple neurotransmitter targets associated with the alcoholism disease. The coming decade promises more powerful tools for characterizing drug effects on alcohol drinking, thereby closing the gap between animal models of addiction and the human condition.

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D-methamphetamine is abused for its euphoric effects and stimulatory action on cognitive function. Its abuse can, however, be associated with massive hypertension resulting in strokes, ruptured aneurysms, or myocardial infarction. We examined the utility of isradipine, a dihydropyridine-class calcium channel antagonist, in treating d-methamphetamine induced hypertension and evaluated its effects on cognitive function, both of which are mediated by dopaminergic mechanisms. D-methamphetamine dose-dependently increased all vital signs (systolic, diastolic, and mean arterial pressure, and pulse rate) parameters. Isradipine significantly reduced d-methamphetamine-induced increases in diastolic and mean arterial pressure; however, this potentially beneficial therapeutic effect was offset by a significant reflex rise in pulse rate. D-methamphetamine also improved attention, accuracy of reasoning ability, and performance on computerized cognitive function tasks. D-methamphetamine's cognitive improving effects were not altered significantly by isradipine. Isradipine increased the false responding rate but was without significant effect on any other attentional task, or on reasoning ability, or performance. Isradipine does not appear to enhance cognitive function in healthy humans.

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1. The authors studied the effects of isradipine, a dihydropyridine-class calcium channel antagonist, on d-methamphetamine-induced changes in somatic and psychological perceptions of hunger state using a placebo-controlled, double-blind, Latin Square, cross-over design in 18 healthy volunteers. 2. D-methamphetamine significantly decreased these subjective ratings of hunger, presumably by increasing monoaminergic turnover. 3. Effects on hunger are hypothesized to be mediated by norepinephrine primarily, while dopamine plays only a modest role. Isradipine alone, an inhibitor of dopamine release, had no significant effect on the hunger measures. Additionally, isradipine pretreatment did not significantly alter d-methamphetamine's anorexic effects. 4. Isradipine may, therefore, not significantly modify the control of hunger in humans.

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