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.

Giant Left Ventricular Pseudoaneurysm and Myocardial Dissection as a Complication of Multiple Ventricular Tachycardia Ablations in a Patient with Cardiac Sarcoidosis.

Late development of left ventricular (LV) pseudoaneurysms after ventricular tachycardia (VT) catheter ablation is a rare phenomenon, and very few cases have been reported in the medical literature. We describe the case of a giant LV pseudoaneurysm as a late complication of multiple epicardial and endocardial VT ablations in a female in her 50s with known cardiac sarcoidosis.

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.

Adherence monitoring in naltrexone pharmacotherapy trials: a systematic review.

OBJECTIVE: The efficacy of naltrexone (Revia, Vivitrol) for the treatment of alcohol dependence exhibits a high degree of heterogeneity. The aim of the current study was to evaluate the extent to which variability in patient adherence to treatment contributed to the range of clinical responses observed during naltrexone treatment. METHOD: A systematic review was conducted of efficacy trials of naltrexone for the treatment of alcohol dependence to evaluate the level of adherence monitoring. RESULTS: Of 49 identified trials, 22 (49%) met the inclusion criteria of being randomized, double-blind, placebo-controlled trials that reported adherence. The "adherence-assurance score" of these trials was calculated as a function of the frequency with which "low," "moderate," or "high" confidence levels of adherence monitoring were used. Of these 22 randomized, controlled trials, only 3 (14%) met criteria for high levels of adherence assurance, 5 (23%) met medium adherenceassurance criteria, and 14 (64%) met low adherence criteria. Of the three high-assurance studies, one used direct supervision of thrice-weekly oral dosing of naltrexone, and two used extended-release injectable formulations of naltrexone administered once per month. The Spearman correlation between risk ratios for return to heavy drinking (for naltrexone vs. placebo) and the level of adherence assurance (low vs. medium vs. high) was significant (r = -.62, p = .025). CONCLUSIONS: These findings suggest that the modest effect sizes for naltrexone reported in systematic reviews and meta-analyses may be attributable, at least in part, to variability in naltrexone adherence rates. High-assurance adherence strategies should be standard practice in clinical trials of medications being evaluated for the treatment of alcohol dependence.

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.

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

We report here the results of a randomized, controlled trial evaluating the efficacy of a semiautomated performance improvement system ("patient feedback") that enables real-time monitoring of patient outcomes in outpatient substance abuse treatment clinics. The study involved 118 clinicians working at 20 community-based outpatient substance abuse treatment clinics in the northeast United States. Ten clinics received 12 weeks of the patient feedback performance improvement intervention, and 10 clinics received no intervention during the 12 weeks. More than 1,500 patients provided anonymous ratings of therapeutic alliance, treatment satisfaction, and drug/alcohol use. There was no evidence of an intervention effect on the primary drug and alcohol use scales. There was also no evidence of an intervention effect on secondary measures of therapeutic alliance. Clinician-rated measures of organizational functioning and job satisfaction also showed no intervention effect. Possible insights from these findings and alternative methods of utilizing feedback reports to enhance clinical outcomes are proposed.

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.

Online illegal drug use information: an exploratory analysis of drug-related website viewing by adolescents.

Given the uncertain effects of antidrug media campaigns, and the ease of finding online illegal drug information, research is needed on the Internet role in disseminating drug information to youths. This exploratory study analyzes National Survey of Parents and Youth (NSPY) data on drug website viewing among 12-18 year olds (N = 7,145). Approximately 10.4% reported drug-related website exposure: 5.4% viewed only websites that communicated how to avoid drugs or bad things about drugs (antidrug websites); 1.7% only viewed websites that communicated how to use drugs and good things about drugs (prodrug websites); and 3.2% viewed both types of websites. The low rates of viewing antidrug websites occurred despite efforts in the National Youth Antidrug Media Campaign (NYAMC) to encourage youths to visit such websites. Prodrug website viewers had used inhalants and been offered marijuana, perceived little risk in trying marijuana, intended to use marijuana, had close friends who used drugs, reported low parental monitoring, and had been exposed to antidrug media messages. Viewing antidrug websites was related to gender, income, likelihood of using marijuana in the next 12 months, having close friends who use drugs and talking to friends about avoiding drugs, parental monitoring, and drug prevention exposure. Prior prevention exposure increased drug website viewing overall, perhaps by increasing general curiosity about drugs. Because adolescents increasingly seek health information online, research is needed on how they use the Internet as a drug information source, the temporal relationships of prevention exposure and drug website viewing, and the effects of viewing prodrug websites on drug risk.

Implementing evidence-based practices in community treatment programs: initial feasibility of a counselor "toolkit".

Community substance abuse treatment programs face many barriers to adopting "evidence-based" therapies. Training budgets are inadequate to permit acquisition of complex skills, there is little clinical supervision available, and almost all counseling is done in group sessions. The authors adopted an approach widely used in the teaching field-developing a resource "toolkit" for a specific topic, in this case, a Decisional Balance exercise often used in the evidence-based treatment approach of Motivational Interviewing. This trial toolkit was comprised of a DVD (televised during group to illustrate the clinical concept), a laminated counselor guide (to provide guidance and talking points for the counselor during group), and some worksheets and wallet cards for patients to retain key points (see Table 1). A feasibility trial assessed the acceptability, and sustainability of the "Decisional Balance" concept toolkit among 26 counselors and 210 of their patients, from 6 community-based substance abuse treatment programs. The great majority of patients (97%) and all counselors (100%) reported they were satisfied with the toolkit session; 84% of patients said they would like more groups like the toolkit session. Almost all counselors (96%) were still using at least one component of the toolkit 3 months after their initial exposure with no prompting. The toolkit curriculum-based approach may be a viable and attractive way of translating core concepts from sophisticated evidence-based therapies into use by counselors within contemporary, community-based treatment programs with minimal training.

The effects of extended-release naltrexone on holiday drinking in alcohol-dependent patients.

A post hoc analysis examined the effect of extended-release naltrexone (XR-NTX) treatment combined with psychosocial support on alcohol consumption during holiday and nonholiday periods in a cohort of alcohol-dependent patients who had maintained at least 4 days of continuous abstinence before receiving their first treatment. Three parameters of drinking behavior were examined: percentage of drinking days, percentage of heavy drinking days, and the number of drinks per day. Patients receiving XR-NTX 380 mg reported significantly lower median percentages of drinking days, heavy drinking days, and the number of drinks per day compared with the placebo group. Patients treated with XR-NTX 190 mg reported similar results overall. The results suggest that treatment with XR-NTX 380 mg in combination with psychosocial intervention leads to significant reductions in alcohol consumption, with some measures indicating abstinence in alcohol-dependent patients with initial abstinence during holiday periods.

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.

The availability and portrayal of stimulants over the Internet.

PURPOSE: To quantify the online availability and portrayal of amphetamine-class prescription stimulants with a focus on those medications commonly prescribed to and abused by adolescents. METHOD: The Google search engine was used in searches to assess the frequency of web sites offering to sell controlled stimulants (retail sites) or web sites that directly linked to retail sites (portal sites). In addition separate searches were used to evaluate the portrayal of controlled prescription stimulants by the initial 20 web sites returned by Google. Retail and portal web site frequency was collected for each search. For searches measuring the portrayal of stimulants, web pages were categorized as pro-use, anti-misuse, neutral or other, based on set criteria. RESULTS: Sites offering to sell stimulants without a prescription were found for nearly all search terms. Across all searches, the Schedule III stimulants indicated for the treatment of obesity returned more sites offering to sell stimulants without a prescription than Schedule II stimulants indicated for the treatment of attention-deficit hyperactivity disorder (ADHD). Internet site portrayal of each stimulant varied; however sites that contained "methamphetamine" often included anti-misuse information. CONCLUSIONS: The apparent availability of stimulants over the Internet without a prescription indicates the potential for a significant public health problem. The extent to which teens are obtaining these drugs via the Internet remains unclear, but clinicians must be aware of the potential for abuse, concomitant prescription use issues, illicit sources, and diversion of these medications, which can be highly addictive. Education of consumers and physicians as well as further governmental interventions are needed to limit the potential scope of this problem.

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.

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.

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.