Tubulin modulating antifungal and antiproliferative pyrazinone derivatives.

A novel class of synthetic tubulin polymerization disruptors, based on a substituted pyrazin-2-one core, has been discovered. These molecules have proven to be potent broad spectrum fungicides, with activity on agriculturally important ascomycete and basidiomycete pathogens. They have also been found to be particularly potent against human rhabdomyosarcoma cells. Using an efficient synthetic route, the agricultural and medicinal activity was explored.

Live birth after blastocyst transfer following only 2 days of progesterone administration in an agonadal oocyte recipient.

In oocyte donation cycles where hormone replacement is given to recipients, progesterone administration is necessary to induce the luteal phase and synchronize the endometrium with the embryo stage. Most studies suggest that 5-7 days of progesterone are needed to prepare the endometrium for a day-5 embryo transfer and provide optimal implantation rate. This paper reports a case where an agonadal oocyte recipient received only 2 days of progesterone prior to the embryo transfer of a day-5 embryo. She subsequently had a clinical pregnancy and a live birth.

Nonprescription steroids on the Internet.

This study evaluated the degree to which anabolic-androgenic steroids are proffered for sale over the Internet and how they are characterized on popular Web sites. Searches for specific steroid product labels (e.g., Dianabol) between March 2006 and June 2006 revealed that approximately half of the Web sites advocated their "safe" use, and roughly one third offered to sell them without prescriptions. The Web sites frequently presented misinformation about steroids and minimized their dangers. Less than 5% of the Web sites presented accurate health risk information about steroids or provided information to abusers seeking to discontinue their steroid use. Implications for education, prevention, treatment, and policy are discussed.

Cross-border reproductive care: a clinician's perspective.

Cross-border reproductive care (CBRC) is a means to an end. Nearly all patients' reproductive journeys are designed to deliver them a child, which, for the multitude of reasons discussed in the last issue of this journal, has not been proven possible for them in their home country. Their journey pathways look like the route maps in airline in-flight magazines, but at the end of their flight a medical procedure awaits, often involving a third-party donor or surrogate. Clinicians therefore are tightly involved in the delivery of CBRC, whether as service providers or service facilitators, and have a unique ethical responsibility to ensure that appropriate standards of care are provided to all those receiving treatment, be they patients or third-party providers. Several authors in the symposium issue are rightly critical of exploitation of third parties, particularly in the global south, although some are critical of the use of third-party fertility treatment in principle. However, CBRC and the subsequent fragmentation of fertility treatment is likely to increase and doctors must be drivers for improvement of standards of reproductive medical care in the developing world, and elsewhere, as more countries and clinics seek to benefit economically from the expanding market in medical consumerism.

Efficacy of extended-release naltrexone in patients with relatively higher severity of alcohol dependence.

BACKGROUND: Because some literature reviews have suggested that naltrexone's benefit may be limited to less-severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence, we examined the efficacy of once per month, injectable extended-release naltrexone (XR-NTX 380 mg) in patients with relatively higher severity alcohol dependence. METHODS: Post hoc analyses examined data from a multicenter, placebo-controlled, 24-week randomized trial of XR-NTX for alcohol dependence (N = 624). We analyzed treatment effects in alcohol-dependent patients who had higher baseline severity, as measured by: (i) the Alcohol Dependence Scale (ADS) or (ii) having been medically detoxified in the week before randomization. Efficacy was also examined via the relationship between pretreatment severity indices and reporting at least 4 days of lead-in abstinence prior to treatment-a major predictor of good outcome in the original study. RESULTS: Higher severity alcohol-dependent patients, defined by the ADS, when receiving XR-NTX 380 mg (n = 50) compared with placebo (n = 47), had significantly fewer heavy-drinking days in-trial (hazard ratio=0.583; p = 0.0049) and showed an average reduction of 37.3% in heavy-drinking days compared with 27.4% for placebo-treated patients (p = 0.039). Among those who had a detoxification just prior to randomization, these reductions were 48.9% (XR-NTX 380 mg; n = 11) and 30.9% (placebo; n = 15) (p = 0.004). Subjects with at least 4 days of pretreatment abstinence (n = 82) versus those without (n = 542) had significantly higher pretreatment ADS scores (p = 0.002) and were more likely to require detoxification prior to randomization (p < 0.001). Patients with lead-in abstinence experienced significantly better maintenance of initial and 6-month abstinence. CONCLUSIONS: These secondary analyses support the efficacy of XR-NTX 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence, with implications for the role of adherence pharmacotherapy.

Long-term opioid blockade and hedonic response: preliminary data from two open-label extension studies with extended-release naltrexone.

The emergence of extended-release naltrexone (XR-NTX) raises the opportunity to explore the role of endorphin blockade on hedonic response during long-term alcohol dependence treatment. A hedonic survey was administered to 74 alcohol dependent patients treated for an average of 3.5 years with nearly continuous month-long intramuscular XR-NTX. The paper-and-pencil, one-time survey asked patients about the degree of pleasure they experienced in the past 90 days with drinking alcohol, sex, exercise and other daily activities. The data revealed lower pleasure ratings for alcohol than for sex, exercise and 10 other common activities. Mean responses to drinking alcohol and gambling were significantly lower than to listening to music, sex, reading, being with friends, eating good food, eating spicy food, and playing video/card games. This effect was independent of XR-NTX dose or duration. Although this exploratory study lacked baseline data, a comparison group or control for the impact of patient discontinuation, the data indicate the feasibility of examining long-term hedonic response in recovery. The differential hedonic ratings suggest that, in patients who persist with long-term continuous therapy, XR-NTX may selectively inhibit the pleasure associated with drinking alcohol, compared to a variety of other activities.

Availability of websites offering to sell psilocybin spores and psilocybin.

This study assesses the availability of websites offering to sell psilocybin spores and psilocybin, a powerful hallucinogen contained in Psilocybe mushrooms. Over a 25-month period beginning in March 2003, eight searches were conducted in Google using the term "psilocybin spores." In each search the first 100 nonsponsored links obtained were scored by two independent raters according to standardized criteria to determine whether they offered to sell psilocybin or psilocybin spores. No attempts were made to procure the products offered for sale in order to ascertain whether the marketed psilocybin was in fact "genuine" or "counterfeit." Of the 800 links examined, 58% led to websites offering to sell psilocybin spores. Additionally, evidence that whole Psilocybe mushrooms are offered for sale online was obtained. Psilocybin and psilocybin spores were found to be widely available for sale over the Internet. Online purchase of psilocybin may facilitate illicit use of this potent psychoactive substance. Additional studies are needed to assess whether websites offering to sell psilocybin and psilocybin spores actually deliver their products as advertised.

Treatment programs in the National Drug Abuse Treatment Clinical Trials Network.

Drug abuse treatment programs and university-based research centers collaborate to test emerging therapies for alcohol and drug disorders in the National Drug Abuse Treatment Clinical Trials Network (CTN). Programs participating in the CTN completed Organizational Surveys (n=106 of 112; 95% response rate) and Treatment Unit Surveys (n=348 of 384; 91% response rate) to describe the levels of care, ancillary services, patient demographics, patient drug use and co-occurring conditions. Analyses describe the corporations participating in the CTN and provide an exploratory assessment of variation in treatment philosophies. A diversity of treatment centers participate in the CTN; not for profit organizations with a primary mission of treating alcohol and drug disorders dominate. Compared to National Survey of Substance Abuse Treatment Services (N-SSATS), programs located in medical settings are over-represented and centers that are mental health clinics are under-represented. Outpatient, methadone, long-term residential and inpatient treatment units differed on patients served and services provided. Larger programs with higher counselor caseloads in residential settings reported more social model characteristics. Programs with higher social model scores were more likely to offer self-help meetings, vocational services and specialized services for women. Conversely, programs with accreditation had less social model influence. The CTN is an ambitious effort to engage community-based treatment organizations into research and more fully integrate research and practice.

Internet access to Salvia divinorum: implications for policy, prevention, and treatment.

This study determined the degree to which Salvia divinorum, a potent hallucinogenic drug that is legal in most U.S. jurisdictions, is being proffered for sale over the Internet and how it is being characterized on popular Web sites. Search results revealed that between one half and two thirds (58%) of the Web sites either offered to sell S. divinorum or linked to other Web sites offering to sell the drug and that more than three quarters (78%) of the Web sites advocated for its use. Many of the statements issued on the Web sites were erroneous or falsely interpreted the absence of scientific data on the possible side effects of S. divinorum as evidence that no side effect exists. The portrayal and availability of S. divinorum on the Internet are similar to those of other illicit and prescription drugs of abuse. However, much less is known about the short- and long-term effects of this novel drug. Consequently, there is little basis to contradict the many Web sites that encourage its use. Implications for drug policy, prevention, and treatment are discussed.

Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial.

CONTEXT: The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful. OBJECTIVE: To evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth. DESIGN, SETTING, AND PATIENTS: Clinical trial at 6 community programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone or a 14-day taper (detox). INTERVENTIONS: Patients in the 12-week buprenorphine-naloxone group were prescribed up to 24 mg per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg per day and then tapered to day 14. All were offered weekly individual and group counseling. MAIN OUTCOME MEASURE: Opioid-positive urine test result at weeks 4, 8, and 12. RESULTS: The number of patients younger than 18 years was too small to analyze separately, but overall, patients in the detox group had higher proportions of opioid-positive urine test results at weeks 4 and 8 but not at week 12 (chi(2)(2) = 4.93, P = .09). At week 4, 59 detox patients had positive results (61%; 95% confidence interval [CI] = 47%-75%) vs 58 12-week buprenorphine-naloxone patients (26%; 95% CI = 14%-38%). At week 8, 53 detox patients had positive results (54%; 95% CI = 38%-70%) vs 52 12-week buprenorphine-naloxone patients (23%; 95% CI = 11%-35%). At week 12, 53 detox patients had positive results (51%; 95% CI = 35%-67%) vs 49 12-week buprenorphine-naloxone patients (43%; 95% CI = 29%-57%). By week 12, 16 of 78 detox patients (20.5%) remained in treatment vs 52 of 74 12-week buprenorphine-naloxone patients (70%; chi(2)(1) = 32.90, P < .001). During weeks 1 through 12, patients in the 12-week buprenorphine-naloxone group reported less opioid use (chi(2)(1) = 18.45, P < .001), less injecting (chi(2)(1) = 6.00, P = .01), and less nonstudy addiction treatment (chi(2)(1) = 25.82, P < .001). High levels of opioid use occurred in both groups at follow-up. Four of 83 patients who tested negative for hepatitis C at baseline were positive for hepatitis C at week 12. CONCLUSIONS: Continuing treatment with buprenorphine-naloxone improved outcome compared with short-term detoxification. Further research is necessary to assess the efficacy and safety of longer-term treatment with buprenorphine for young individuals with opioid dependence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00078130.

Reduction in heavy drinking as a treatment outcome in alcohol dependence.

In the field of clinical alcohol disorders treatment in North America, abstinence continues to be largely viewed as the optimal treatment goal; however, there is a growing awareness of limitations when abstinence is considered the only successful outcome. Although this issue has been discussed in research settings, new studies on the public health significance of heavy drinking (defined as five or more standard drinks per drinking day in men, and four or more standard drinks per drinking day in women) in the past 10 years suggest that clinical providers should consider the value of alternative outcomes besides abstinence. A focus on abstinence as the primary outcome fails to capture the impact of treatment on reduction in the pattern and in the frequency of alcohol consumption. In addition, evaluating reduction in drinking as "positive" has value for patients as an indicator of clinical progress. Measurement of continuous variables, such as the quantity and the frequency of alcohol consumption, has provided a clearer understanding of the scope of alcohol-related morbidity and mortality at the societal level, and of the relationship between individual patient characteristics and the naturalistic course of alcohol use, abuse, and dependence. A review of these characteristics suggests that there are clinical benefits associated with reducing heavy drinking in alcohol-dependent patients. Given the significant public health consequences associated with heavy drinking and the benefits associated with its reduction, it is proposed that researchers, public health professionals, and clinicians consider using reduction in heavy drinking as a meaningful clinical indicator of treatment response, and that outcomes be individualized to patients' goals and readiness to change.

A feasibility study of a web-based performance improvement system for substance abuse treatment providers.

We report here on the feasibility of implementing a semiautomated performance improvement system-Patient Feedback (PF)-that enables real-time monitoring of patient ratings of therapeutic alliance, treatment satisfaction, and drug/alcohol use in outpatient substance abuse treatment clinics. The study was conducted in six clinics within the National Institute on Drug Abuse Clinical Trials Network. It involved a total of 39 clinicians and 6 clinic supervisors. Throughout the course of the study (consisting of five phases: training period [4 weeks], baseline [4 weeks], intervention [12 weeks], postintervention assessment [4 weeks], sustainability [1 year]), there was an overall collection rate of 75.5% of the clinic patient census. In general, the clinicians in these clinics had very positive treatment satisfaction and alliance ratings throughout the study. However, one clinic had worse drug use scores at baseline than other participating clinics and showed a decrease in self-reported drug use at postintervention. Although the implementation of the PF system proved to be feasible in actual clinical settings, further modifications of the PF system are needed to enhance any potential clinical usefulness.

Direct care workers in the National Drug Abuse Treatment Clinical Trials Network: characteristics, opinions, and beliefs.

OBJECTIVE: Individuals with direct care responsibilities in 348 drug abuse treatment units were surveyed to obtain a description of the workforce and to assess support for evidence-based therapies. METHODS: Surveys were distributed to 112 programs participating in the National Drug Abuse Treatment Clinical Trials Network (CTN). Descriptive analyses characterized the workforce. Analyses of covariance tested the effects of job category on opinions about evidence-based practices and controlled for the effects of education, modality (outpatient or residential), race, and gender. RESULTS: Women made up two-thirds of the CTN workforce. One-third of the workforce had a master's or doctoral degree. Responses from 1,757 counselors, 908 support staff, 522 managers-supervisors, and 511 medical staff (71% of eligible participants) suggested that the variables that most were most consistently associated with responses were job category (19 of 22 items) and education (20 of 22 items). Managers-supervisors were the most supportive of evidence-based therapies, and support staff were the least supportive. Generally, individuals with graduate degrees had more positive opinions about evidence-based therapies. Support for using medications and contingency management was modest across job categories. CONCLUSIONS: The relatively traditional beliefs of support staff could inhibit the introduction of evidence-based practices. Programs initiating changes in therapeutic approaches may benefit from including all employees in change efforts.

The availability of web sites offering to sell opioid medications without prescriptions.

OBJECTIVE: This study was designed to determine the availability of web sites offering to sell opioid medications without prescriptions. METHOD: Forty-seven Internet searches were conducted with a variety of opioid medication terms, including "codeine," "no prescription Vicodin," and "OxyContin." Two independent raters examined the links generated in each search and resolved any coding disagreements. The resulting links were coded as "no prescription web sites" (NPWs) if they offered to sell opioid medications without prescriptions. RESULTS: In searches with terms such as "no prescription codeine" and "Vicodin," over 50% of the links obtained were coded as "NPWs." The proportion of links yielding NPWs was greater when the phrase "no prescription" was added to the opioid term. More than 300 opioid NPWs were identified and entered into a database. CONCLUSIONS: Three national drug-use monitoring studies have cited significant increases in prescription opioid use over the past 5 years, particularly among young people. The emergence of NPWs introduces a new vector for unregulated access to opioids. Research is needed to determine the effect of NPWs on prescription opioid use initiation, misuse, and dependence.

Knowledge and use of the internet as a source of controlled substances.

Despite growing evidence that the internet is a source of controlled substances for nonmedical use, there is a lack of information about who is using it to obtain these drugs. One hundred adult drug-dependent inpatients in a private residential treatment program participated in a semistructured interview regarding how they obtained their drugs. Twenty-nine percent reported knowledge of the internet as a source of drugs, and 11% reported that they had used the internet to either buy drugs or locate a drug dealer. The results of this preliminary study suggest that the internet has become a source of controlled substances for some addicted individuals. Considerations for future research and clinical practice are described.

Innovations: Alcohol & drug abuse: Narcotics on the net: the availability of Web sites selling controlled substances.

The Internet is not only a vital medium for communication, entertainment, and commerce, but it is also an outlet for illicit drug sales. Although the U.S. Controlled Substances Act regulates access to certain drugs by requiring prescriptions, unique characteristics of the Internet create significant challenges for the enforcement of U.S. drug policies. In the late 1990s "no prescription Web sites" (NPWs) began to emerge, which allow persons to purchase drugs, such as opiates, without a prescription. Given the likely role of NPWs in increasing prescription drug abuse, health care professionals must develop and disseminate strategies for helping patients who are affected by these Web sites.

Cardiogenic shock caused by right ventricular infarction: a report from the SHOCK registry.

OBJECTIVES: The purpose of this study was to determine the characteristics and outcomes of patients with acute myocardial infarction (MI) complicated by cardiogenic shock due to predominant right ventricular (RV) infarction. BACKGROUND: Although RV infarction has been shown to have favorable long-term outcomes, the influence of RV infarction on mortality in cardiogenic shock is unknown. METHODS: We evaluated 933 patients in cardiogenic shock due to predominant RV (n = 49) or left ventricular (LV) failure (n = 884) in the SHould we emergently revascularize Occluded coronaries for Cardiogenic shocK? (SHOCK) trial registry. RESULTS: Patients with predominant RV shock were younger, with a lower prevalence of previous MI (25.5 vs. 40.1%, p = 0.047), anterior MI, and multivessel disease (34.8 vs. 77.8%, p < 0.001) and a shorter median time between the index MI and the diagnosis of shock (2.9 vs. 6.2 h, p = 0.003) in comparison to patients with LV shock. In-hospital mortality was 53.1% versus 60.8% (p = 0.296) for patients with predominant RV and LV shock, respectively, and the influence of revascularization on mortality was not different between groups. Multivariate analysis revealed that RV shock was not an independent predictor of lower in-hospital mortality (odds ratio 1.07, 95% confidence interval 0.54 to 2.13). CONCLUSIONS: Despite the younger age, lower rate of anterior MI, and higher prevalence of single-vessel coronary disease of RV compared with LV shock patients, and their similar benefit from revascularization, mortality is unexpectedly high in patients with predominant RV shock and similar to patients with LV shock.

Do patient characteristics and initial progress in treatment moderate the effectiveness of telephone-based continuing care for substance use disorders?

AIMS: To determine whether substance use severity, psychiatric severity, social support, self-help attendance or motivation moderated substance use outcomes in a telephone-based continuing care intervention. DESIGN: A randomized study comparing three 12-week continuing care interventions: weekly telephone monitoring and counseling combined with a support group in the first 4 weeks (TEL), twice-weekly individualized relapse prevention (RP) and twice-weekly standard group counseling (STND). METHODS: Following completion of 4-week intensive out-patient programs (IOP), 359 patients with alcohol and/or cocaine dependence were assigned randomly to a continuing care condition and followed quarterly for 12 months. Ten potential moderator variables were examined in separate analyses. Two of these variables reflected pretreatment status, whereas the other variables were focused on performance while in the IOP. A composite risk measure was also constructed from dichotomized versions of seven of these variables, with higher scores indicating greater potential for relapse. The dependent measures were total abstinence and percentage of days abstinent from alcohol and cocaine in each quarter. FINDINGS: Of 40 interaction contrasts that were examined with individual risk indicator measures, only one reached the 0.05 level of significance. Patients with any alcohol use in IOP had a higher percentage of days abstinence in STND than in TEL. In addition, high scores on the composite risk indicator predicted higher total abstinence rates in STND than in TEL, whereas low to moderate scores predicted higher abstinence rates in TEL than in STND. CONCLUSION: For most graduates of IOPs, the combination of brief weekly telephone therapeutic contacts and a support group in the first month produced outcomes that are as good as those obtained in more intensive face-to-face continuing care interventions. However, patients with current dependence on both alcohol and cocaine who make little progress towards achieving the central goals of IOP may have better outcomes if they receive twice-weekly group counseling following IOP.

Reconsidering the evaluation of addiction treatment: from retrospective follow-up to concurrent recovery monitoring.

Historically, addiction treatments have been delivered and evaluated under an acute-care format. Fixed amounts or durations of treatment have been provided and their effects evaluated 6-12 months after completion of care. The explicit expectation of treatment has been enduring reductions in substance use, improved personal health and social function, generally referred to as 'recovery'. In contrast, treatments for chronic illnesses such as diabetes, hypertension and asthma have been provided for indeterminate periods and their effects evaluated during the course of those treatments. Here the expectations are for most of the same results, but only during the course of continuing care and monitoring. The many similarities between addiction and mainstream chronic illnesses stand in contrast to the differences in the ways addiction is conceptualized, treated and evaluated. This paper builds upon established methods of during-treatment evaluation developed for the treatment of other chronic illnesses and suggests a parallel evaluation system for out-patient, continuing-care forms of addiction treatment. The suggested system retains traditional patient-level, behavioral outcome measures of recovery, but suggests that these outcomes should be collected and reported immediately and regularly by clinicians at the beginning of addiction treatment sessions, as a way of evaluating recovery progress and making decisions about continuing care. We refer to this paradigm as 'concurrent recovery monitoring' and discuss its potential for producing more timely, efficient, clinically relevant and accountable evaluations.

Assisted reproductive technology: 25 years of progress.

Great strides have been made in assisted reproductive technology and nearly all forms of subfertility are now amenable to treatment. Constant advances in technology and ethical controversy ensure it has a high public profile. The impact of assisted reproductive technology will be discussed in this article.